Substituted octahydropyrrolo[1,2-a]pyrazine sulfonamides as calcium channel blockers

ABSTRACT

The present application relates to: (a) compounds of Formula (I): 
                         
and salts thereof, wherein Z′, Z″, L 2 , G 2 , R 1 , and R 2  are as defined in the specification; (b) compositions comprising such compounds and salts; and (c) methods of use of such compounds, salts, and compositions, particularly use as calcium channel blockers.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent application claims priority to U.S. Provisional PatentApplication No. 61/540,716 (filed Sep. 29, 2011). The entire text ofthat provisional application is incorporated by reference into thisapplication.

TECHNICAL FIELD

The present application relates to compounds that are calcium channelblockers, compositions comprising such compounds, and methods oftreating conditions and disorders using such compounds and compositions.

BACKGROUND

Voltage-gated calcium channels (VGCC) play an integral role in theregulation of membrane ion conductance, neurotransmitter release, andcellular excitability. VGCC are composed of the pore-forming α1 subunitand auxiliary α2δ and β subunits that modulate channel expression andfunctional properties (Dolphin, A. C. British Journal of Pharmacology2006, 147 (Suppl. 1), S56-S62). These channels can be classified intolow-voltage activated (LVA; T-type or Ca_(v)3.x) and high-voltageactivated (HVA; L-type or Ca_(v)1.x and N-, P/Q- and R-types orCa_(v)2.x) channels. N-, P/Q and R channels typically activate at morepositive membrane potentials (˜−30 mV) and are involved in “presynaptic”neurotransmission (McGivern J. G. Drug Discovery Today 2006, 11,245-253). T-type channels are activated at relatively negative membranepotentials (˜−60 mV) and are primarily involved in “postsynaptic”excitability (Shin, H.-S.; et al. Curr. Opin. in Pharmacology 2008, 8,33-41).

N-type channel α₁ subunits are encoded by a single gene (α₁B orCa_(v)2.2) in contrast to pharmacologically defined L- and T-typecurrents that are encoded by multiple α₁-subunit genes. A diversity ofN-type channels arises due to extensive alternative splicing of the αsubunit gene that generates variants with different expression patternsand GPCR-modulated biophysical properties (Gray, A. C.; et al. CellCalcium, 2007, 42(4-5), 409-417). The primary sequence for Ca_(v)2.2 ishighly conserved across species (rat and human share 91% identity at theamino acid level).

N-type channels are widely expressed in the central nervous system (CNS)(cortex, hippocampus, striatum, thalamus, brain stem nuclei and spinalcord) and in the peripheral nervous system (PNS) (adult sympatheticnervous system and dorsal root ganglia) (Ino, M.; et al. Proc. Natl.Acad. Sci. USA 2001, 98(9), 5323-5328). In pain pathways, N-typechannels are expressed in the rostral ventral medulla, an important siteof descending pain modulation (Urban, M. O.; et al. Neuroreport 2005,16(6), 563-566) and are a major contributor to the synapticneurotransmission that occurs between C/Aδ nociceptors and spinal laminaI neurons (Bao, J.; et al. J. Neurosci. 1998, 18(21), 8740-50. Heinke,B.; et al. Eur. J. Neurosci. 2004, 19(1), 103-111). In contrast, P/Qtype channels are expressed almost exclusively in laminae II-IV of thespinal cord and show little co-localization with Substance P and N-typechannels (Westenbroek, R. E.; et al. J. Neurosci. 1998, 18(16),6319-6330).

Following nerve injury there is increased expression of Ca_(v)2.2(Westenbroek, R. E.; et al. J. Neurosci. 1998, 18(16), 6319-6330.Cizkova, D.; et al. Exp. Brain Res. 2002, 147, 456-463. Yokoyama, K.; etal. Anesthesiology 2003, 99(6), 1364-1370) and α2δ1 subunits (Luo, Z.D.; et al. J. Neurosci. 2001, 21(6), 1868-1875. Newton, R. A.; et al.Mol. Brain. Res. 2001, 95(1-2), 1-8) in addition to increases in thesuperficial layers of the dorsal horn of the spinal cord supporting arole for N-type channels in neuropathic pain. Recently anociceptor-specific Ca_(v)2.2 splice variant has been identified in thedorsal root ganglion (Bell, T. J.; et al. Neuron 2004, 41(1), 127-138).These channels have distinct electrophysiological properties and currentdensities (Castiglioni, A. J.; et al. J. Physiol. 2006, 576(Pt 1),119-134) compared to wildtype Ca_(v)2.2 channels. While G-proteincoupled receptor inhibition of wildtype N-type channels is typicallymediated by Gβγ and is voltage-dependent, the nociceptor specific splicevariant is inhibited by GPCR activation (e.g. opioids) in avoltage-independent fashion (Raingo, J.; et al. Nat. Neurosci. 2007,10(3), 285-292). This mechanism substantially increases the sensitivityof Ca_(v)2.2 channels to opiates and gamma-aminobutyric acid (GABA)suggesting that cell-specific alternative splicing of mRNA for Ca_(v)2.2channels serves as a molecular switch that controls the sensitivity ofN-type channels to neurotransmitters and drugs that modulatenociception. Collectively these data provide further support for therole of Ca_(v)2.2 channels in pain states.

The relative contributions of various HVA Ca²⁺ channels in nociceptivesignaling have been evaluated using knockout mice studies. Ca_(v)2.2knockout mice are healthy, fertile, and do not display overtneurological deficits (Ino, M.; et al. Proc. Natl. Acad. Sci. USA 2001,98(9), 5323-5328. Kim, C.; et al. Mol. Cell. Neurosci. 2001, 18(2),235-245. Hatakeyama, S.; et al. Neuroreport 2001, 12(11), 2423-2427.Liu; L.; et al. J. Bioenerg. Biomembr. 2003, 35(6), 671-685). Thisfinding suggests that other types of Ca_(v) channels are able tocompensate for the lack of Ca_(v)2.2 channels at most synapses in thesemice (Pietrobon, D. Curr. Opin. Neurobiol. 2005, 15(3), 257-265).Ca_(v)2.2 deficient mice are resistant to the development ofinflammatory and neuropathic pain (Kim, C.; et al. Mol. Cell. Neurosci.2001, 18(2), 235-245. Hatakeyama, S.; et al. Neuroreport 2001, 12(11),2423-2427. Saegusa, H.; et al. EMBO J. 2001, 20(10), 2349-2356), havedecreased sympathetic nervous system function (Ino, M.; et al. Proc.Natl. Acad. Sci. USA 2001, 98(9), 5323-5328), and altered responses toboth ethanol and anesthetics (Newton, R. A.; et al. Brain Res. Mol.Brain. Res. 2001, 95(1-2), 1-8. Takei, R. et al. Neurosci. Lett. 2003,350(1), 41-45). Additional behavioral studies indicate that Ca_(v)2.2knockout mice are less anxious, are hyperactive, and show enhancedvigilance compared to wild-type littermates (Beuckmann, C. T.; et al. J.Neurosci. 2003, 23(17), 6793-6797).

N- and P/Q-type channels are localized at neuronal synaptic junctionsand contribute significantly to neurotransmitter release (Olivera, B.M.; et al. Annu. Rev. Biochem. 1994, 63, 823-867. Miljanich, G P.; etal. Annu. Rev. Pharmacol. Toxicol. 1995, 35, 707-734). N-type channelsplay a major role in the release of glutamate, acetylcholine, dopamine,norepinephrine, GABA, substance P and calcitonin gene-related protein(CGRP). P/Q-type channels may be involved in the release of glutamate,aspartate, 5HT, GABA and probably glycine (Pietrobon, D. Curr. Opin.Neurobiol. 2005, 15(3), 257-265).

L, P/Q and N-type channels are blocked by channel specific antagonistsi.e., dihydropyridines, ω-agatoxin WA and ω-conotoxin MVIIA/ziconotide,respectively. Agatoxin IVa has been shown to block excitatory (Luebke,J. I.; et al. Neuron 1993, 11(5), 895-902) as well as inhibitoryneurotransmission (Takahashi, T.; et al. Nature 1993, 366(6451),156-158). Intrathecal injection of selective N-type channel blockers(e.g. conotoxin-derived peptides such as GVIA, MVIIA (ziconotide), andCVID) significantly attenuates pain responses in animal models ofneuropathic pain, formalin-induced pain, and post-operative pain(Chaplan, S. R.; et al. J. Pharmacol. Exp. Ther. 1994, 269(3),1117-1123. Malmberg, A. B.; et al. J. Neurosci. 1994, 14(8), 4882-4890.Bowersox, S. S.; et al. J. Pharmacol. Exp. Ther. 1996, 279(3),1243-1249. Wang, Y. X.; et al. Pain 2000, 84(2-3), 151-158. Scott, D.A.; et al. Eur. J. Pharmacol. 2002, 451(3), 279-286). These peptideblockers bind to the pore region of the channel, do not show voltage- orfrequency-dependent activity, and show irreversible channel block (Feng,Z. P.; et al. J. Biol. Chem. 2003, 278(22), 20171-20178). Ziconotidepotently blocks neurotransmitter release in the spinal cord dorsal horn(Matthews, E. A.; et al. Pain 2001, 92(1-2), 235-246. Smith, M. T.; etal. Pain 2002, 96(1-2), 119-127. Heinke, B.; et al. Eur. J. Neurosci.2004, 19(1), 103-111) and in dorsal root ganglion (DRG) neurons (Evans,A. R.; et al. Brain Res. 1996, 712(2), 265-273. Smith, M. T.; et al.Pain 2002, 96(1-2), 119-127). It also potently and fully blocksdepolarization-induced release of substance P from rat spinal cordslices. In contrast, intrathecal delivery of the selective P/Q typeblocker ω-agatoxin IVA had no effects on mechanical allodynia in thespinal nerve ligation model (Chaplan, S. R.; et al. J. Pharmacol. Exp.Ther. 1994, 269(3), 1117-1123) or thermal hyperalgesia in the chronicconstriction injury model (Yamamoto, T.; et al. Brain Res. 1998, 794(2),329-332) of neuropathic pain.

T-Type or LVA calcium channels are composed of a single pore forming α₁subunit of which there are three subtypes: Cav3.1, Cav3.2 and Cav3.3(Perez-Reyes, E.; et al. J. Pharmacol. Exp. Ther. 2009, 328(2), 621-7).These channels are activated at relatively hyperpolarized cell membranepotentials and contribute to membrane depolarization following actionpotential generation. As a result, T-type calcium channel activationtriggers secondary bursts of neuronal action potentials with increasedaction potential duration. Evidence supporting a role of T-type calciumchannels in neuropathic pain comes from studies that have shown aconcurrent increase in the expression of Cav3.2 channelsafter-depolarization potentials in medium diameter Aδ high thresholdmechanoreceptor dorsal root ganglia (DRG) neurons in diabetic neuropathy(Jagodic, M. M.; et al. J Neurosci 2007, 27, 3305-3316) and in smalldiameter neurons from the chronic constriction injury (CCl) neuropathicpain model (Jagodic, M. M.; et al. J Neurophysiol 2008, 99, 3151-3156).Additional support comes from gene knockdown studies whereby intrathecalCav3.2 antisense administration produces a significant knockdown(˜80-90%) of T-type calcium currents in small and medium diameter DRGneurons, and produces robust anti-allodynic and antihyperalgesic effectsin the CCl rat model of neuropathic pain (Bourinet, E.; et al. Embo J2005, 24, 315-324). Moreover, Cav3.2 knockout mice show decreased painresponses compared to wild-type mice in acute mechanical, thermal, andchemical pain models (Choi, S.; et al. Genes Brain Behav 2007, 6,425-431).

Recently, T-type calcium channel blockers have been proposed to havepotential in treating schizophrenia and substance dependence. The T-typecalcium channels are located in brain regions that have relevance toschizophrenia and substance dependence (Talley, E. M.; et al. J Neurosci1999, 19, 1895-1911). More importantly, it has been demonstrated thatselective T-type calcium channel blockers, such as TTA-A2, haveantipsychotic-like effects in preclinical animal models of psychosis(Uslaner, J. M.; et al. Neuropharmacology 2012, 62, 1413-1421) and wereable to decrease nicotine seeking behavior in rats trained toself-administer nicotine (Uslaner, J. M.; et al. Biol Psychiatry 2010,68, 712-718).

In addition to a role in nociception, T-type calcium channels have alsobeen implicated to play roles in sleep disorders and absence epilepsy(Shin, H.-S.; et al. Curr Opin Pharmacol, 2008, 8, 33-41). Based onexpression in the thalamus, T-type calcium channels may play a role inarousal from sleep (Benington, J. H.; et al. Prog Neurobiol 2003, 69,71-101; Nordskog, B. K.; et al. Neuroscience 2006, 141, 1365-1373).Expression in the adrenal, pituitary and pineal glands suggests thatthese channels modulate hormone secretion. Notably, Cav3.2 knockout miceappear normal and healthy, although smaller than wild-type mice (Chen,C.-C.; et al. Science 2003, 302, 1416-1418; Choi, S.; et al. Genes BrainBehav 2007, 6, 425-431).

Pain is the most common symptom of disease and the most frequentcomplaint with which patients present to physicians. Inadequate painmanagement across the spectrum of pain etiologies remains a major publichealth problem. Going forward, the development of novel therapeuticswith new mechanisms of action for the treatment of pain includingcalcium channel blockade will have a significant impact on the ongoingstruggle to balance efficacy and safety for those patients most in need.The compounds of the present invention are novel calcium channelblockers that have utility in treating pain, amongst other conditions.

SUMMARY OF THE INVENTION

The invention is directed to compounds of Formula (I):

and salts thereof, wherein:

one of Z′ and Z″ is CH₂ and the other of Z′ and Z″ is CH₂ or C(O);

one of R¹ and R² is hydrogen and the other of R¹ and R² is G¹-L¹-;

L¹ is —C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —S(O)₂NR^(a)—,—NR^(a)S(O)₂—; —NR^(a)—, or —O—;

G¹ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹, —(CR^(a)R^(b))_(j)—Ar¹,—CH(Ar¹)₂, or —Ar¹-G^(a);

R^(a) and R^(b), at each occurrence, are each independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl;

R^(c) and R^(d) are each independently hydrogen, hydroxy, C₁-C₄-alkyl,or C₁-C₄-haloalkyl;

j is 1, 2, 3, 4, or 5;

Ar¹ is, at each occurrence, independently aryl or heteroaryl, whereinAr¹ is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsselected from the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, halogen, cyano, —NO₂, —OR^(s), —OC(O)R^(s),—OC(O)N(R^(s))(R^(t)), —SR^(s), —S(O)R^(s), —S(O)₂R^(s),—S(O)₂N(R^(s))(R^(t)), —C(O)R⁵, —C(O)OR^(s), —C(O)N(R^(s))(R^(t)),—N(R^(s))(R^(t)), —N(R^(s))C(O)R^(t), —N(R^(s))C(O)O(R),—N(R^(s))S(O)₂(R), C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl;

R^(s) and R^(t) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl or C₁-C₄-haloalkyl;

G^(a) is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocycle, orheteroaryl, wherein the C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl,heterocycle, or heteroaryl are unsubstituted or substituted with 1, 2,or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen;

L² is —S(O)₂—, —S(O)₂CH₂—, or —S(O)—;

G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-cycloalkyl, Ar² or Ar³;

Ar² is aryl or heteroaryl, wherein Ar² is unsubstituted or substitutedwith 1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, halogen, cyano, —NO₂,—OR^(u), -alkyl-OR^(u), —OC(O)R^(u), —OC(O)N(R^(u))(R^(v)), —SR^(u),—S(O)R^(u), —S(O)₂R^(u), —S(O)₂N(R^(u))(R^(v)), —C(O)R^(u), —C(O)OR^(u),—C(O)N(R^(u))(R^(v)), —N(R^(u))(R^(v)), —N(R^(u))C(O)R^(v),—N(R^(u))C(O)O(R^(v)), —N(R^(u))S(O)₂(R^(v)), C₁-C₄-cyanoalkyl,C₁-C₄-haloalkyl and -G^(b);

G^(b) is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocycle, aryl orheteroaryl, wherein the C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl,heterocycle, aryl or heteroaryl are unsubstituted or substituted with 1,2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen;

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl or C₁-C₄-haloalkyl;

Ar³ is (i), wherein:

X is O, S, NR^(w), or CH₂; wherein R^(w) is hydrogen or alkyl;

Y is C(O) or CH₂;

R^(z) and R^(y) are independently, at each occurrence, hydrogen orC₁-C₄-alkyl; and

m is 1, 2 or 3.

Another aspect of the invention relates to pharmaceutical compositionscomprising therapeutically effective amount of compound(s) of theinvention or pharmaceutically acceptable salts thereof, in combinationwith one or more pharmaceutically acceptable carrier. Such compositionscan be administered in accordance with a method of the invention,typically as part of a therapeutic regimen for treatment or preventionof conditions and disorders related to calcium channels. Moreparticularly, the method is useful for treating conditions related to amethod of treating pain in a subject in need thereof. The methodcomprises administering to the subject a therapeutically suitable amountof a compound of Formula (I), or a pharmaceutically acceptable saltthereof. Conditions related to pain include acute pain, chronic pain,neuropathic pain, inflammatory pain, visceral pain, cancer pain,osteoarthritis pain, allodynia, fibromyalgia, sciatica, back pain, andheadache pain including migraine, or combinations thereof.

Another aspect of the invention provides a method of treating disordersof the central nervous system in a subject in need thereof. The methodcomprising the step of: administering a therapeutically suitable amountof a compound of Formula (I), or a pharmaceutically acceptable saltthereof. The disorders of the central nervous system include stroke;epilepsy; absence epilepsy; manic depression; bipolar disorders;depression; anxiety; schizophrenia; migraine; psychoses; neuraldegenerative disorders including Alzheimer's disease, AIDS relateddementia, Parkinson's disease, neuropathy caused by head injury, anddementia caused by cerebrovascular disorders; and substance dependenceand drug addiction withdrawal symptoms, including ethanol addictionwithdrawal symptoms; or combinations thereof.

Another aspect of the invention provides a method of treating disordersof the lower urinary tract including overactive bladder, prostatis,prostadynia, interstitial cystitis, and benign prostatic hyperplasia;disorders caused by psychogenic stress including bronchial asthma,unstable angina, and hypersensitive colon inflammation; cardiovasculardisorders including hypertension, atherosclerosis, heart failure, andcardiac arrhythmias; skin disorders including pruritis and allergicdermatitis, inflammatory bowel disease; sleep disorders; cancer;diabetes; and infertility and sexual dysfunction, or combinationsthereof. The method comprising the step of: administering atherapeutically suitable amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

The compounds, compositions comprising the compounds, and methods fortreating or preventing conditions and disorders by administering thecompounds are further described herein.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of Formula (I):

and salts thereof, wherein Z′, Z″, L², G², R¹, and R² are as definedabove in the Summary of the Invention. The invention further includescompositions comprising such compounds and methods for treatingconditions and disorders using such compounds and compositions.

In various embodiments, the present invention provides at least onevariable that occurs more than one time in any substituent or in thecompound of the invention or any other formulae herein. Definition of avariable on each occurrence is independent of its definition at anotheroccurrence. Further, combinations of substituents are permissible onlyif such combinations result in stable compounds. Stable compounds arecompounds, which can be isolated from a reaction mixture.

A. DEFINITIONS

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double. Representative examples of alkenylinclude, but are not limited to, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” denotes a divalent group derived from a straightor branched chain hydrocarbon of 2 to 4 carbon atoms and contains atleast one carbon-carbon double bond. Representative examples ofalkenylene include, but are not limited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “loweralkyl” or “C₁₋₆ alkyl” means a straight or branched chain hydrocarboncontaining 1 to 6 carbon atoms. The term “C₁₋₃ alkyl” means a straightor branched chain hydrocarbon containing 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylene” denotes a divalent group derived from a straight orbranched chain hydrocarbon 1 to 10 carbon atoms. Representative examplesof alkylene include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Representative examplesof the biaryl groups include, but are not limited to, dihydroindenyl,indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. Thebicyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the bicyclic ring system. The aryl groupsof the present invention can be unsubstituted or substituted.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of cyanoalkyl include, butare not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkyl” or “cycloalkane” as used herein, means amonocyclic, a bicyclic, or a tricyclic cycloalkyl. The monocycliccycloalkyl is a carbocyclic ring system containing three to eight carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is a monocycliccycloalkyl fused to a monocyclic cycloalkyl ring, or a bridgedmonocyclic ring system in which two non-adjacent carbon atoms of themonocyclic ring are linked by an alkylene bridge containing one, two,three, or four carbon atoms. Representative examples of bicyclic ringsystems include, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic cycloalkylsare exemplified by a bicyclic cycloalkyl fused to a monocycliccycloalkyl, or a bicyclic cycloalkyl in which two non-adjacent carbonatoms of the ring systems are linked by an alkylene bridge of 1, 2, 3,or 4 carbon atoms. Representative examples of tricyclic-ring systemsinclude, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonane(octahydro-2,5-methanopentalene or noradamantane), andtricyclo[3.3.1.1^(3,7)]decane (adamantane). The monocyclic, bicyclic,and tricyclic cycloalkyls can be unsubstituted or substituted, and areattached to the parent molecular moiety through any substitutable atomcontained within the ring system.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “cycloalkenyl” or “cycloalkene” as used herein, means amonocyclic or a bicyclic hydrocarbon ring system. The monocycliccycloalkenyl has four-, five-, six-, seven- or eight carbon atoms andzero heteroatoms. The four-membered ring systems have one double bond,the five- or six-membered ring systems have one or two double bonds, andthe seven- or eight-membered ring systems have one, two or three doublebonds. Representative examples of monocyclic cycloalkenyl groupsinclude, but are not limited to, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl and cyclooctenyl. The bicyclic cycloalkenylis a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, ora monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. Themonocyclic or bicyclic cycloalkenyl ring can contain one or two alkylenebridges, each consisting of one, two or three carbon atoms, each linkingtwo non-adjacent carbon atoms of the ring system. Representativeexamples of the bicyclic cycloalkenyl groups include, but are notlimited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems, and can be unsubstituted orsubstituted.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkyl include, butare not limited to, chloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and trifluoropropyl such as3,3,3-trifluoropropyl.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic heterocycle, a bicyclic heterocycle, or a tricyclicheterocycle. The monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S. Thethree- or four-membered ring contains zero or one double bond, and oneheteroatom selected from the group consisting of O, N, and S. Thefive-membered ring contains zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. Thesix-membered ring contains zero, one or two double bonds and one, two,or three heteroatoms selected from the group consisting of O, N, and S.The seven- and eight-membered rings contains zero, one, two, or threedouble bonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl,1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, andtrithianyl. The bicyclic heterocycle is a monocyclic heterocycle fusedto a phenyl group, or a monocyclic heterocycle fused to a monocycliccycloalkyl, or a monocyclic heterocycle fused to a monocycliccycloalkenyl, or a monocyclic heterocycle fused to a monocyclicheterocycle, or a bridged monocyclic heterocycle ring system in whichtwo non adjacent atoms of the ring are linked by an alkylene bridge of1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, orfour carbon atoms. Representative examples of bicyclic heterocyclesinclude, but are not limited to, benzopyranyl, benzothiopyranyl,chromanyl, 2,3-dihydrobenzofuranyl, 3,4-dihydrobenzothienyl,2,3-dihydroisoquinolinyl or indolinyl, 2,3-dihydroisoquinolinyl,1,1-dioxidoisothiazolidinyl, azabicyclo[2.2.1]heptyl (including2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro-1H-indolyl, isoindolinyl,octahydro-1H-indolyl, octahydrocyclopenta[c]-pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but are not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). The monocyclic, bicyclic, andtricyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl or abicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered ring. The five-membered ring contains two double bonds. Thefive-membered ring can contain one heteroatom selected from O or S; orone, two, three, or four nitrogen atoms and optionally one oxygen orsulfur atom. The six-membered ring contains three double bonds and one,two, three or four nitrogen atoms. Representative examples of monocyclicheteroaryl include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl,tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, andtriazinyl. The bicyclic heteroaryl consists of a monocyclic heteroarylfused to a phenyl, or a monocyclic heteroaryl fused to a monocycliccycloalkyl, or a monocyclic heteroaryl fused to a monocycliccycloalkenyl, or a monocyclic heteroaryl fused to a monocyclicheteroaryl, or a monocyclic heteroaryl fused to a monocyclicheterocycle. Representative examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzothienyl,benzoxazolyl, 2,1,3-benzothiadiazolyl, benzimidazolyl, benzoxadiazolyl,6,7-dihydro-1,3-benzothiazolyl, furo[3,2-b]pyrrolyl,imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl,naphthyridinyl, pyridoimidazolyl, pyrrolopyridinyl, quinolinyl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl,thienopyridinyl and 5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic andbicyclic heteroaryl groups of the present invention can be substitutedor unsubstituted and are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the ringsystems.

The term “heteroarylalkyl,” as used herein, means a heteroaryl groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “heteroatom” as used herein, means a nitrogen, oxygen, orsulfur atom.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “nitro” as used herein, means a —NO₂ group.

The term “nitrogen protecting group” as used herein means those groupsintended to protect a nitrogen atom against undesirable reactions duringsynthetic procedures. Nitrogen protecting groups comprise carbamates,amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogenprotecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz),formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc),tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).Nitrogen-protecting groups are appended onto primary or secondary aminogroups by reacting the compound that contains the amine group with base,such as triethylamine, and a reagent selected from an alkyl halide, analkyl triflate, a dialkyl anhydride, for example as represented by analkyl anhydride (alkyl-OC═O)₂O, a diaryl anhydride, for example asrepresented by (aryl-OC═O)₂O, an acyl halide, an alkylchloroformate, oran alkylsulfonylhalide, an arylsulfonylhalide, or halo-CON(alkyl)₂, forexample acetyl chloride, benzoyl chloride, benzyl bromide,benzyloxycarbonyl chloride, formylfluoride, phenylsulfonyl chloride,pivaloyl chloride, (tert-butyl-O—C═O)₂O, trifluoroacetic anhydride, andtriphenylmethyl chloride.

The term “oxo” as used herein, means a ═O group.

When cycloalkyl, heterocycle, heteroaryl, aryl, and the like are“substituted”, it means there are one or more substituents other thanhydrogen on the respective ring. “Unsubstituted” rings have nosubstituents other than hydrogen.

In some instances, the number of carbon atoms in a hydrocarbonsubstituent (e.g., alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl)is indicated by the prefix “C_(x)—C_(y)”, wherein x is the minimum and yis the maximum number of carbon atoms in the substituent. Thus, forexample, “C₁-C₆-alkyl” refers to an alkyl substituent containing from 1to 6 carbon atoms. Illustrating further, C₃-C₆-cycloalkyl means asaturated hydrocarbon ring containing from 3 to 6 carbon ring atoms.

B. COMPOUNDS

Compounds of the invention have the Formula (I) as described above.

Particular values of variable groups in compounds of Formula (I) are asfollows. Such values can be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

More particularly, compounds of Formula (I) can include, but are notlimited to compounds wherein both of Z′ and Z″ are CH₂. Such compoundscan be shown as having the alternative structure of Formula (I-A):

In another embodiment, Z′ is CH₂ and Z″ is C(O).

In another embodiment, Z′ is C(O) and Z″ is CH₂.

In another embodiment, R¹ is hydrogen and R² is G¹-L¹-.

In another embodiment, R¹ is G¹-L¹- and R² is hydrogen.

In another embodiment, the invention is directed to compounds of Formula(I-A) wherein:

one of R¹ and R² is hydrogen and the other of R¹ and R² is G¹-L¹-;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, —S(O)₂NR^(a)—, —NR^(a)S(O)₂—;—NR^(a)—, or —O—;

G¹ is C₁-C₈-alkyl, C₁-C₈ haloalkyl Ar¹, —(CR^(a)R^(b))_(j)—Ar¹,—CH(Ar¹)₂ or —Ar¹-G^(a);

R^(a) and R^(b), at each occurrence, are each independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl;

j is 1, 2, 3, 4, or 5;

Ar¹ is, at each occurrence, independently aryl or heteroaryl, whereinAr¹ is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsselected from the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, halogen, cyano, —NO₂, —OR^(s), —OC(O)R^(s),—OC(O)N(R^(s))(R^(t)), —SRS, —S(O)R^(s), —S(O)₂R^(s),—S(O)₂N(R^(s))(R^(t)), —C(O)R^(s), —C(O)OR^(s), —C(O)N(R^(s))(R^(t)),—N(R^(s))(R^(t)), —N(R^(s))C(O)R^(t), —N(R^(s))C(O)O(R^(t)),—N(R^(s))S(O)₂(R^(t)), C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl;

R^(s) and R^(t) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl or C₁-C₄-haloalkyl;

G^(a) is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocycle, orheteroaryl, wherein the C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl,heterocycle, or heteroaryl are unsubstituted or substituted with 1, 2,or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen;

L² is —S(O)₂—, or —S(O)—;

G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-cycloalkyl, Ar² or Ar³;

Ar² is aryl or heteroaryl, wherein Ar² is unsubstituted or substitutedwith 1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, halogen, cyano, —NO₂,—OR^(u), -alkyl-OR^(u), —OC(O)R^(u), —OC(O)N(R^(u))(R^(v)), —SR^(u),—S(O)R^(u), —S(O)₂R^(u), —S(O)₂N(R^(u))(R^(v)), —C(O)R^(u), —C(O)OR^(u),—C(O)N(R^(u))(R^(v)), —N(R^(u))(R^(v)), —N(R^(u))C(O)R^(v),—N(R^(u))C(O)O(R^(v)), —N(R^(u))S(O)₂(R^(v)), C₁-C₄-cyanoalkyl,C₁-C₄-haloalkyl and -G^(b);

G^(b) is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocycle, aryl orheteroaryl, wherein the C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl,heterocycle, aryl or heteroaryl are unsubstituted or substituted with 1,2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen;

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl or C₁-C₄-haloalkyl;

Ar³ is (i), wherein:

X is O, S, NR^(w), or CH₂; wherein R^(w) is hydrogen or alkyl;

Y is C(O) or CH₂;

R^(z) and R^(y) are hydrogen; and

m is 1, 2 or 3.

In one embodiment, L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, —S(O)₂NR^(a)—,—NR^(a)S(O)₂—; —NR^(a)—, or —O—.

In another embodiment, L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or—O—.

In another embodiment, L¹ is —S(O)₂NR^(a)— or —NR^(a)S(O)₂—.

In another embodiment, L¹ is —C(O)NR^(a)— or —NR^(a)C(O)—.

In another embodiment, L¹ is —C(O)NR^(a)— or —NR^(a)C(O)—, wherein R^(a)is hydrogen.

In another embodiment, L¹ is —NR^(a)—.

In another embodiment, L¹ is —NR^(a)—, wherein R^(a) is hydrogen.

In a further embodiment, L¹ is —O—.

In one embodiment, G¹ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹,—(CR^(a)R^(b))_(j)—Ar¹, —CH(Ar¹)₂ or —Ar¹-G^(a).

In another embodiment, G¹ is C₁-C₈-alkyl.

In another embodiment, G¹ is C₁-C₈-haloalkyl, Ar¹,—(CR^(a)R^(b))_(j)—Ar¹, —CH(Ar¹)₂ or —Ar¹-G^(a).

In another embodiment, G¹ is C₁-C₈-haloalkyl.

In another embodiment, G¹ is Ar¹.

In another embodiment, G¹ is Ar¹, wherein Ar¹ is aryl or heteroaryloptionally substituted as described below.

In another embodiment, G¹ is —(CR^(a)R^(b))_(j)—Ar¹.

In another embodiment, G¹ is —(CR^(a)R^(b))_(j)—Ar¹, wherein R^(a) andR^(b) are each hydrogen, j is 1, and Ar¹ is aryl or heteroaryloptionally substituted as described below.

In another embodiment, G¹ is —CH(Ar¹)₂.

In another embodiment, G¹ is —CH(Ar¹)₂, wherein Ar¹ is, at eachoccurrence, independently aryl or heteroaryl optionally substituted asdescribed below.

In another embodiment, G¹ is —Ar¹-G^(a).

In another embodiment, G¹ is —Ar¹-G^(a), wherein Ar¹ is aryl orheteroaryl optionally substituted as described below, and G^(a) isC₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocycle, or heteroaryl,wherein the C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocycle, orheteroaryl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl,C₁-C₄-haloalkyl, or halogen.

In another embodiment, G¹ is —Ar¹-G^(a), wherein Ar¹ is aryl orheteroaryl optionally substituted as described below, and G^(a) isC₃-C₇-cycloalkyl or heteroaryl, wherein the C₃-C₇-cycloalkyl orheteroaryl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl,C₁-C₄-haloalkyl, or halogen.

In another embodiment, G¹ is —Ar¹-G^(a), wherein Ar¹ is aryl orheteroaryl optionally substituted as described below, and G^(a) isheteroaryl, wherein the heteroaryl is unsubstituted or substituted with1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen.

In a further embodiment, G¹ is —Ar¹-G^(a), wherein Ar¹ is aryl orheteroaryl optionally substituted as described below, and G^(a) iscyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl areunsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl,C₁-C₄-haloalkyl, or halogen.

In one embodiment, R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₄-alkyl, or C₁-C₄-haloalkyl.

In another embodiment, R^(a) and R^(b), at each occurrence, are eachindependently hydrogen or C₁-C₄-alkyl.

In another embodiment, R^(a) and R^(b), at each occurrence, are eachC₁-C₄-haloalkyl.

In another embodiment, R^(a) and R^(b), at each occurrence, are eachC₁-C₄-alkyl.

In a further embodiment, R^(a) and R^(b), at each occurrence, are eachhydrogen.

In one embodiment, j is 1, 2, 3, 4, or 5.

In another embodiment, j is 1, 2 or 3.

In a further embodiment, j is 1.

In one embodiment, Ar¹ is, at each occurrence, independently aryl orheteroaryl, wherein Ar¹ is unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl, halogen, cyano, —NO₂, —OR^(s),—OC(O)R^(s), —OC(O)N(R^(s))(R^(t)), —SR^(s), —S(O)R^(s), —S(O)₂R^(s),—S(O)₂N(R^(s))(R^(t)), —C(O)R^(s), —C(O)OR^(s), —C(O)N(R^(s))(R^(t)),—N(R^(s))(R^(t)), —N(R^(s))C(O)R^(t), —N(R^(s))C(O)O(R^(t)),—N(R^(s))S(O)₂(R^(t)), C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl; whereinR^(s) and R^(t) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl or C₁-C₄-haloalkyl.

In another embodiment, Ar¹ is aryl, wherein Ar¹ is unsubstituted orsubstituted with 1, 2 or 3 substituents selected from the groupconsisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, halogen, cyano, —OR^(s), andC₁-C₄-haloalkyl; wherein R^(s) is hydrogen, C₁-C₄-alkyl orC₁-C₄-haloalkyl.

In a further embodiment, Ar¹ is heteroaryl, wherein Ar¹ is unsubstitutedor substituted with 1, 2 or 3 substituents selected from the groupconsisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, halogen, cyano, —OR^(s), andC₁-C₄-haloalkyl; wherein R^(s) is hydrogen, C₁-C₄-alkyl orC₁-C₄-haloalkyl.

In one embodiment, G^(a) is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl,heterocycle, or heteroaryl, wherein the C₃-C₇-cycloalkyl,C₃-C₇-cycloalkenyl, heterocycle, or heteroaryl are unsubstituted orsubstituted with 1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen.

In another embodiment, G^(a) is C₃-C₇-cycloalkyl or heteroaryl, whereinthe C₃-C₇-cycloalkyl or heteroaryl are unsubstituted or substituted with1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen.

In another embodiment, G^(a) is heteroaryl, wherein the heteroaryl isunsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl,C₁-C₄-haloalkyl, or halogen.

In another embodiment, G^(a) is C₃-C₇-cycloalkyl, wherein theC₃-C₇-cycloalkyl is unsubstituted or substituted with 1, 2, or 3C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen.

In a further embodiment, G^(a) is cyclopropyl or cyclobutyl, wherein thecyclopropyl or cyclobutyl are unsubstituted or substituted with 1, 2, or3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen.

In one embodiment, L² is —S(O)₂—, or —S(O)—.

In another embodiment, L² is —S(O)—.

In a further embodiment, L² is —S(O)₂—.

In one embodiment, G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-cycloalkyl,Ar² or Ar³.

In another embodiment, G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl orC₁-C₈-cycloalkyl.

In another embodiment, G² is Ar² or Ar³, wherein Ar² and Ar³ are asdescribed below.

In another embodiment, G² is Ar², wherein Ar² is as described below.

In a further embodiment, G² is Ar³, wherein Ar³ is as described below.

In one embodiment, Ar² is aryl or heteroaryl, wherein Ar² isunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,halogen, cyano, —NO₂, —OR^(u), -alkyl-OR^(u), —OC(O)R^(u),—OC(O)N(R^(u))(R^(v)), —SR^(u), —S(O)R^(u), —S(O)₂R^(u),—S(O)₂N(R^(u))(R^(v)), —C(O)R^(u), —C(O)OR^(u), —C(O)N(R^(u))(R^(v)),—N(R^(u))(R^(v)), —N(R^(u))C(O)R^(v), —N(R^(u))C(O)O(R^(v)),—N(R^(u))S(O)₂(R^(v)), C₁-C₄-cyanoalkyl, C₁-C₄-haloalkyl and -G^(b);G^(b) is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocycle, aryl orheteroaryl, wherein the C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl,heterocycle, aryl or heteroaryl are unsubstituted or substituted with 1,2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen; and R^(u) and R^(v)are, at each occurrence, independently hydrogen, C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl or C₁-C₄-haloalkyl.

In another embodiment, Ar² is aryl wherein Ar² is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, halogen, cyano,—NO₂, —OR^(u), -alkyl-OR^(u), —OC(O)R^(u), —OC(O)N(R^(u))(R^(v)),—SR^(u), —S(O)R^(u), —S(O)₂R^(u), —S(O)₂N(R^(u))(R^(v)), —C(O)R^(u),—C(O)OR^(u), —C(O)N(R^(u))(R^(v)), —N(R^(u))(R^(v)), —N(R^(u))C(O)R^(v),—N(R^(u))C(O)O(R^(v)), —N(R^(u))S(O)₂(R^(v)), C₁-C₄-cyanoalkyl,C₁-C₄-haloalkyl and -G^(b); G^(b) is C₃-C₇-cycloalkyl,C₃-C₇-cycloalkenyl, heterocycle, aryl or heteroaryl, wherein theC₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocycle, aryl or heteroarylare unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl,C₁-C₄-haloalkyl, or halogen; and R^(u) and R^(v) are, at eachoccurrence, independently hydrogen, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl or C₁-C₄-haloalkyl.

In another embodiment, Ar² is phenyl or naphthyl, wherein Ar² isunsubstituted or substituted with 1, 2, or 3 substituents selected fromthe group consisting of C₁-C₄-alkyl, halogen, cyano, —OR^(u),-alkyl-OR^(u), —C(O)R^(u), C₁-C₄-haloalkyl and -G^(b); G^(b) isC₃-C₇-cycloalkyl, heterocycle, aryl or heteroaryl, wherein theC₃-C₇-cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted orsubstituted with 1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen;and R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl or C₁-C₄-haloalkyl.

In another embodiment, Ar² is phenyl or naphthyl, wherein Ar² isunsubstituted or substituted with 1, 2, or 3 substituents selected fromthe group consisting of C₁-C₄-alkyl, halogen, cyano, —OR^(u),-alkyl-OR^(u), —C(O)R^(u), C₁-C₄-haloalkyl and -G^(b); G^(b) isC₃-C₇-cycloalkyl, heterocycle, aryl or heteroaryl, wherein theC₃-C₇-cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted orsubstituted with 1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen;and R^(u) is hydrogen, C₁-C₄-alkyl or C₁-C₄-haloalkyl.

In a further embodiment, Ar² is heteroaryl, wherein Ar² is unsubstitutedor substituted with 1, 2, or 3 substituents selected from the groupconsisting of C₁-C₄-alkyl, halogen, cyano, —OR^(u), -alkyl-OR^(u),—C(O)R^(u), C₁-C₄-haloalkyl and -G^(b); G^(b) is C₃-C₇-cycloalkyl,heterocycle, aryl or heteroaryl, wherein the C₃-C₇-cycloalkyl,heterocycle, aryl or heteroaryl are unsubstituted or substituted with 1,2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen; and R^(u) is hydrogen,C₁-C₄-alkyl or C₁-C₄-haloalkyl.

In one embodiment, Ar³ is (i), wherein:

X is O, S, NR^(w), or CH₂; 127 is hydrogen or alkyl; Y is C(O) or CH₂;R^(z) and R^(y) are hydrogen; and m is 1, 2 or 3.

In another embodiment, Ar³ is (i), wherein:

X is O, NR^(w), or CH₂; R^(w) is hydrogen or alkyl; Y is C(O) or CH₂;R^(z) and R^(y) are hydrogen; and m is 1, 2 or 3.

In another embodiment, Ar³ is (i), wherein:

X is O or S; Y is CH₂; R^(z) and R^(y) are hydrogen; and m is 1 or 2.

In another embodiment, Ar³ is (i), wherein:

X is NR^(w); R^(w) is hydrogen or alkyl; Y is C(O) or CH₂; R^(z) andR^(y) are hydrogen; and m is 1, 2 or 3.

In another embodiment, Ar³ is (i), wherein:

X is NR^(w); R^(w) is alkyl; Y is C(O); R^(z) and R^(y) are hydrogen;and m is 1.

In another embodiment, Ar³ is (i), wherein:

X is CH₂; Y is C(O) or CH₂; R^(z) and R^(y) are hydrogen; and m is 1, 2or 3.

In another embodiment, Ar³ is (i), wherein:

X is CH₂; Y is CH₂; R^(z) and R^(y) are hydrogen; and m is 1 or 2.

In one embodiment, in a compound of Formula (I) or Formula (I-A): R¹ isG¹-L¹-; L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, —S(O)₂NR^(a)—, or—NR^(a)S(O)₂—; R² is hydrogen; and L² is —S(O)₂—.

In another embodiment, in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; R² is hydrogen; L¹ is —C(O)NR^(a)— or —NR^(a)C(O)—; G¹ isC₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹, —(CR^(a)R^(b))_(j)—Ar¹, or —CH(Ar¹)₂;R^(a) and R^(b), at each occurrence, are each independently hydrogen orC₁-C₄-alkyl; L² is —S(O)₂— and G² is Ar² or Ar³.

In further embodiment, in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; R² is hydrogen; L¹ is —C(O)NR^(a)— or —NR^(a)C(O)—; G¹ isC₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹, —(CR^(a)R^(b))_(j)—Ar¹, or —CH(Ar¹)₂;R^(a) and R^(b), at each occurrence, are each independently hydrogen orC₁-C₄-alkyl; Ar¹ is, at each occurrence, independently aryl orheteroaryl, wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3substituents selected from the group consisting of C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl, halogen, cyano, —OR^(s), —SR^(s),—C(O)R^(s), C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl; R^(s) is hydrogen,C₁-C₄-alkyl, C₂-C₄-alkenyl or C₁-C₄-haloalkyl; L² is —S(O)₂—; G² is Ar²;Ar² is aryl or heteroaryl, wherein Ar² is unsubstituted or substitutedwith 1, 2, or 3, substituents selected from the group consisting ofC₁-C₄-alkyl, halogen, cyano, —C(O)R^(u), C₁-C₄-cyanoalkyl,C₁-C₄-haloalkyl and -G^(b); G^(b) is C₃-C₂-cycloalkyl, heterocycle, arylor heteroaryl, wherein the C₃-C₂-cycloalkyl, C₃-C₂-cycloalkenyl,heterocycle, aryl or heteroaryl are unsubstituted or substituted with 1,2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen; and R″ is C₁-C₄-alkyl,or C₁-C₄-haloalkyl.

In one embodiment, in a compound of Formula (I) or Formula (I-A): R¹ isG¹-L¹-; L¹ is NR^(a)—; R^(a) is hydrogen, C₁-C₄-alkyl, orC₁-C₄-haloalkyl; R² is hydrogen; and L² is —S(O)₂—.

In another embodiment, in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; L¹ is NR^(a); R^(a) is hydrogen; R² is hydrogen; L² is—S(O)₂—; G¹ is Ar¹; Ar¹ is aryl or heteroaryl, wherein Ar¹ isunsubstituted or substituted with 1, 2, or 3 substituents selected fromthe group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,halogen, cyano, —OR^(s), —SR^(s), —C(O)R^(s), C₁-C₄-cyanoalkyl, andC₁-C₄-haloalkyl; R^(s) is, at each occurrence, independently hydrogen,C₁-C₄-alkyl, C₂-C₄-alkenyl or C₁-C₄-haloalkyl; G² is Ar²; Ar² is aryl orheteroaryl, wherein Ar² is unsubstituted or substituted with 1, 2, or 3,substituents selected from the group consisting of C₁-C₄-alkyl, halogen,cyano, —C(O)R^(u), C₁-C₄-cyanoalkyl, C₁-C₄-haloalkyl and -G^(b); G^(b)is C₃-C₇-cycloalkyl, heterocycle, aryl or heteroaryl, wherein theC₃-C₇-cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted orsubstituted with 1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen;and is C₁-C₄-alkyl, or C₁-C₄-haloalkyl.

In one embodiment, in a compound of Formula (I) or Formula (I-A): R¹ ishydrogen; R² is G¹-L¹-; L¹ is —O—; and L² is —S(O)₂—.

In another embodiment, in a compound of Formula (I) or Formula (I-A): R¹is hydrogen; R² is G¹-L¹-; L¹ is —O—; G¹ is Ar¹; Ar¹ is aryl orheteroaryl, wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3substituents selected from the group consisting of C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl, halogen, cyano, —OR^(s), —SR^(s),—C(O)R^(s), C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl; R^(s) is, at eachoccurrence, independently hydrogen, C₁-C₄-alkyl, C₂-C₄-alkenyl orC₁-C₄-haloalkyl; L² is —S(O)₂—; G² is Ar²; Ar² is aryl or heteroaryl,wherein Ar² is unsubstituted or substituted with 1, 2, or 3,substituents selected from the group consisting of C₁-C₄-alkyl, halogen,cyano, —C(O)R^(u), C₁-C₄-cyanoalkyl, C₁-C₄-haloalkyl and -G^(b); G^(b)is C₃-C₇-cycloalkyl, heterocycle, aryl or heteroaryl, wherein theC₃-C₇-cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted orsubstituted with 1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen;and is C₁-C₄-alkyl, or C₁-C₄-haloalkyl.

In one embodiment, in a compound of Formula (I) or Formula (I-A): R¹ isG¹-L¹-; L¹ is —O—; R² is hydrogen; and L² is —S(O)₂—.

In another embodiment, in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; L¹ is —O—; G¹ is Ar¹, —(CR^(a)R^(b))_(j)—Ar¹, —CH(Ar¹)₂, and—Ar¹-G^(a); R^(a) and R^(b), at each occurrence, are each independentlyhydrogen or C₁-C₄-alkyl; R² is hydrogen; L² is —S(O)₂—; and G² is Ar² orAr³.

In another embodiment, in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; L¹ is —O—; G¹ is Ar¹; Ar¹ is aryl or heteroaryl, wherein Ar¹is unsubstituted or substituted with 1, 2, or 3 substituents selectedfrom the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, halogen, cyano,—OR^(s), —C(O)R^(s), C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl; R^(s) isC₁-C₄-alkyl or C₁-C₄-haloalkyl; R² is hydrogen; L² is —S(O)₂—; G² isAr²; Ar² is aryl or heteroaryl, wherein Ar² is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from the groupconsisting of C₁-C₄-alkyl, halogen, cyano, —C(O)R^(u), C₁-C₄-cyanoalkyl,and C₁-C₄-haloalkyl; and R^(u) is C₁-C₄-alkyl or C₁-C₄-haloalkyl.

In another embodiment, in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; L¹ is —O—; G¹ is —(CR^(a)R^(b))_(j)—Ar¹; R^(a) and R^(b), ateach occurrence, are each independently hydrogen or C₁-C₄-alkyl; j is 1,2 or 3; Ar¹ is aryl or heteroaryl, wherein Ar¹ is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from the groupconsisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, halogen, cyano, —OR^(s),—C(O)R^(s), C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl; R^(s) is C₁-C₄-alkylor C₁-C₄-haloalkyl; R² is hydrogen; L² is —S(O)₂—; G² is Ar²; Ar² isaryl or heteroaryl, wherein Ar² is unsubstituted or substituted with 1,2, or 3 substituents selected from the group consisting of C₁-C₄-alkyl,halogen, cyano, —C(O)R^(u), C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl; andis C₁-C₄-alkyl or C₁-C₄-haloalkyl.

In another embodiment, in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; L¹ is —O—; G¹ is —Ar¹-G^(a); Ar¹ is aryl or heteroaryl,wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl,halogen, cyano, —OR^(s), —C(O)R^(s), C₁-C₄-cyanoalkyl, andC₁-C₄-haloalkyl; R^(s) is C₁-C₄-alkyl or C₁-C₄-haloalkyl; G^(a) isheteroaryl, wherein the heteroaryl is unsubstituted or substituted with1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen; R² is hydrogen; L²is —S(O)₂—; G² is Ar²; Ar² is aryl or heteroaryl, wherein Ar² isunsubstituted or substituted with 1, 2, or 3 substituents selected fromthe group consisting of C₁-C₄-alkyl, halogen, cyano, —C(O)R^(u),C₁-C₄-cyanoalkyl, and C₁-C₄-haloalkyl; and R^(a) is C₁-C₄-alkyl orC₁-C₄-haloalkyl.

In another embodiment in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; L¹ is —O—; G¹ is —Ar¹-G^(a); Ar¹ is aryl or heteroaryl,wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl,halogen, cyano, —OR^(s), —C(O)R^(s), C₁-C₄-cyanoalkyl, andC₁-C₄-haloalkyl; R^(s) is C₁-C₄-alkyl or C₁-C₄-haloalkyl; G^(a) isC₃-C₂-cycloalkyl, wherein the C₃-C₂-cycloalkyl is unsubstituted orsubstituted with 1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen; R²is hydrogen; L² is —S(O)₂—; G² is Ar²; Ar² is aryl or heteroaryl,wherein Ar² is unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄-alkyl,C₂-C₄-alkenyl, halogen, cyano, —C(O)R^(a), C₁-C₄-cyanoalkyl,C₁-C₄-haloalkyl and -G^(b); G^(b) is C₃-C₂-cycloalkyl, heterocycle, arylor heteroaryl, wherein the C₃-C₇-cycloalkyl, heterocycle, aryl orheteroaryl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl,C₁-C₄-haloalkyl, or halogen; and R^(u) is C₁-C₄-alkyl orC₁-C₄-haloalkyl.

In another embodiment, in a compound of Formula (I) or Formula (I-A): R¹is G¹-L¹-; L¹ is —O—; G¹ is —Ar¹-G^(a); Ar¹ is aryl or heteroaryl,wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl,halogen, cyano, —OR^(u), —C(O)R^(s), C₁-C₄-cyanoalkyl, andC₁-C₄-haloalkyl; R⁵ is C₁-C₄-alkyl or C₁-C₄-haloalkyl; G^(a) isC₃-C₇-cycloalkyl, wherein the C₃-C₇-cycloalkyl is unsubstituted orsubstituted with 1, 2, or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen; R²is hydrogen; L² is —S(O)₂—; G² is Ar³; Ar³ is (i):

wherein X is O, NR^(w), or CH₂; R^(w) is hydrogen or alkyl; Y is C(O) orCH₂; R^(z) and R^(y) are hydrogen; and m is 1, 2 or 3.

(i) Additional Embodiments G¹ and G² Aryl and Heteroaryl Substituents

In one embodiment, the invention is directed to compounds of Formula (I)or Formula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—;

G¹ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹, —(CR^(a)R^(b))—Ar¹, —CH(Ar¹)₂,or —Ar¹-G^(a);

R^(a) and R^(b), at each occurrence, are each hydrogen;

R^(c) and R^(d) are each independently hydrogen or hydroxy;

Ar¹ is, at each occurrence, independently selected from the groupconsisting of phenyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and benzoxazolyl; wherein Ar¹ is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂— or —S(O)₂CH₂—;

G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-cycloalkyl, Ar², or Ar³;

Ar² is aryl or heteroaryl; wherein the Ar² aryl is selected from thegroup consisting of phenyl, naphthyl, and tetrahydronaphthylenyl; theAr² heteroaryl is selected from the group consisting of furyl, thienyl,pyrazolyl, and pyridinyl; and Ar² is unsubstituted or substituted with1, 2, 3, 4, or 5 substituents selected from the group consisting ofhalogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u),—C(O)OR^(u), —C(O)N(R^(u))(R^(v)), and -G^(b);

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl;

Ar³ is dihydroindenyl, dihydrobenzofuranyl, orhexahydropyrrolo[1,2-a]-pyrazinyl; wherein the dihydroindenyl,dihydrobenzofuranyl, and hexahydropyrrolo[1,2-a]-pyrazinyl areunsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl or oxo.

In another embodiment, the invention is directed to compounds of Formula(I) or Formula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—;

G¹ is —Ar¹ or —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

R^(c) and R^(d) are each independently hydrogen or hydroxy;

Ar¹ is, at each occurrence, independently selected from the groupconsisting of phenyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and benzoxazolyl; wherein Ar¹ is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from the groupconsisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂— or —S(O)₂CH₂—;

G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-cycloalkyl, Ar², or Ar³;

Ar² is aryl or heteroaryl; wherein the Ar² aryl is selected from thegroup consisting of phenyl, naphthyl, and tetrahydronaphthylenyl; theAr² heteroaryl is selected from the group consisting of furyl, thienyl,pyrazolyl, and pyridinyl; and Ar² is unsubstituted or substituted with1, 2, or 3 substituents selected from the group consisting of halogen,cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u), —C(O)OR^(u),—C(O)N(R^(u))(R^(v)), and -G^(b);

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl;

Ar³ is dihydroindenyl, dihydrobenzofuranyl, orhexahydropyrrolo[1,2-a]pyrazinyl; wherein the dihydroindenyl,dihydrobenzofuranyl, and hexahydropyrrolo[1,2-a]pyrazinyl areunsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl or oxo.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—;

G¹ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹, —(CR^(a)R^(b))—Ar¹, —CH(Ar¹)₂,or —Ar¹-G^(a);

R^(a) and R^(b), at each occurrence, are each hydrogen;

R^(c) and R^(d) are each independently hydrogen or hydroxy;

Ar¹ is, at each occurrence, independently selected from the groupconsisting of phenyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and benzoxazolyl; wherein Ar¹ is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂— or —S(O)₂CH₂—;

G² is Ar²;

Ar² is aryl or heteroaryl; wherein the Ar² aryl is selected from thegroup consisting of phenyl, naphthyl, and tetrahydronaphthylenyl; theAr² heteroaryl is selected from the group consisting of furyl, thienyl,pyrazolyl, and pyridinyl; and Ar² is unsubstituted or substituted with1, 2, 3, 4, or 5 substituents selected from the group consisting ofhalogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u),—C(O)OR^(u), —C(O)N(R^(u))(R^(v)), and -G^(b);

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;and

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl.

In further embodiments of each of the above embodiments, L¹ is—C(O)N(H)—. In further embodiments of each of the above embodiments, L¹is —N(H)C(O)—. In further embodiments of each of the above embodiments,L¹ is —O—.

(ii) Additional Embodiments G¹=Ar¹ or Ar¹-G^(a) and G²=Ar²

In one embodiment, the invention is directed to compounds of Formula (I)or Formula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

Ar¹ is, at each occurrence, independently phenyl, pyridinyl, orpyrazinyl; wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3substituents selected from the group consisting of halogen, cyano,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂—;

G² is Ar²;

Ar² is phenyl or pyridinyl; wherein Ar² is unsubstituted or substitutedwith 1, 2, or 3 substituents selected from the group consisting ofhalogen, cyano, C₁-C₄-alkyl, C₁-C⁴-haloalkyl, —OR^(u), —C(O)R^(u),—C(O)OR^(u), —C(O)N(R^(u))(R^(v)), and -G^(b);

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;and

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

Ar¹ is, at each occurrence, independently phenyl, pyridin-2-yl, orpyrazin-2-yl; wherein Ar¹ is unsubstituted or substituted with 1 or 2substituents selected from the group consisting of halogen, C₁-C₄-alkyl,halomethyl, and halomethoxy;

G^(a) is cyclopropyl;

L² is —S(O)₂—;

G² is Ar²; and

Ar² is phenyl or pyridinyl; wherein Ar² is unsubstituted or substitutedwith 1 or 2 substituents selected from the group consisting of halogen,cyano, C₁-C₄-alkyl, halomethyl, methoxy, and halomethoxy.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

Ar¹ is pyrazin-2-yl; wherein Ar¹ is unsubstituted or substituted with 1or 2 substituents selected from the group consisting of halogen,C₁-C₄-alkyl, halomethyl, and halomethoxy;

G^(a) is cyclopropyl;

L² is —S(O)₂—;

G² is Ar²; and

Ar² is phenyl or pyridinyl; wherein Ar² is substituted with 1 or 2substituents selected from the group consisting of chloro, fluoro,trifluoromethyl, and trifluoromethoxy.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

Ar¹ is phenyl, pyridin-2-yl, or pyrazin-2-yl; wherein Ar¹ substitutedwith 1 or 2 substituents selected from the group consisting of chloro,fluoro, trifluoromethyl, and trifluoromethoxy;

G^(a) is cyclopropyl;

L² is —S(O)₂—; and

Ar² is phenyl; wherein Ar² is substituted with 1 or 2 substituentsselected from the group consisting of chloro, fluoro, trifluoromethyl,and trifluoromethoxy.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

Ar¹ is phenyl, pyridin-2-yl, or pyrazin-2-yl; wherein Ar¹ substitutedwith 1 or 2 substituents selected from the group consisting of chloro,fluoro, trifluoromethyl, and trifluoromethoxy;

G^(a) is cyclopropyl;

L² is —S(O)₂;

Ar² is pyridinyl; wherein Ar² is substituted with 1 or 2 substituentsselected from the group consisting of chloro, fluoro, trifluoromethyl,and trifluoromethoxy.

In further embodiments of each of the above embodiments, L¹ is—C(O)N(H)—.

In further embodiments of each of the above embodiments, L¹ is—N(H)C(O)—. In further embodiments of each of the above embodiments, L¹is —O—.

(iii) Additional Embodiments G¹=C₁-C₈-Alkyl or C₁-C₈-Haloalkyl

In one embodiment, the invention is directed to compounds of Formula (I)or Formula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—;

G¹ is C₁-C₈-alkyl or C₁-C₈-haloalkyl;

R^(c) and R^(d) are each independently hydrogen or hydroxy;

Ar¹ is, at each occurrence, independently selected from the groupconsisting of phenyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and benzoxazolyl; wherein Ar¹ is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from the groupconsisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂— or —S(O)₂;

G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-cycloalkyl, Ar², or Ar³;

Ar² is aryl or heteroaryl; wherein the Ar² aryl is selected from thegroup consisting of phenyl, naphthyl, and tetrahydronaphthylenyl; theAr² heteroaryl is selected from the group consisting of furyl, thienyl,pyrazolyl, and pyridinyl; and Ar² is unsubstituted or substituted with1, 2, or 3 substituents selected from the group consisting of halogen,cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u), —C(O)OR^(u),—C(O)N(R^(u))(R^(v)), and -G^(b);

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl;

Ar³ is dihydroindenyl, dihydrobenzofuranyl, orhexahydropyrrolo[1,2-a]-pyrazinyl; wherein the dihydroindenyl,dihydrobenzofuranyl, and hexahydropyrrolo[1,2-a]-pyrazinyl areunsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl or oxo.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is C₁-C₈-alkyl or C₁-C₈-haloalkyl;

R^(a), at each occurrence, is hydrogen;

L² is —S(O)₂—;

G² is Ar²;

Ar² is phenyl or pyridinyl; wherein Ar² is unsubstituted or substitutedwith 1, 2, or 3 substituents selected from the group consisting ofhalogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u),—C(O)OR^(u), —C(O)N(R^(u))(R^(v)), and -G^(b);

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;and

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is C₁-C₈-alkyl or C₁-C₈-haloalkyl;

R^(a), at each occurrence, is hydrogen;

L² is —S(O)₂—;

G² is Ar²;

Ar² is phenyl or pyridinyl; wherein Ar² is unsubstituted or substitutedwith 1 or 2 substituents selected from the group consisting of halogen,cyano, C₁-C₄-alkyl, halomethyl, methoxy, and halomethoxy.

In further embodiments of each of the above embodiments, L¹ is—C(O)N(H)—. In further embodiments of each of the above embodiments, L¹is —N(H)C(O)—. In further embodiments of each of the above embodiments,L¹ is —O—.

(iv) Additional Embodiments G²=C₁-C₈-Alkyl, C₁-C₈-Haloalkyl, orC₁-C₈-Cycloalkyl

In one embodiment, the invention is directed to compounds of Formula (I)or Formula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—;

G¹ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹, —(CR^(a)R^(b))—Ar¹, —CH(Ar¹)₂,or —Ar¹-G^(a);

R^(a) and R^(b), at each occurrence, are each hydrogen;

R^(c) and R^(d) are each independently hydrogen or hydroxy;

Ar¹ is, at each occurrence, independently selected from the groupconsisting of phenyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and benzoxazolyl; wherein Ar¹ is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂—; and

G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, or C₁-C₈-cycloalkyl.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

Ar¹ is, at each occurrence, independently phenyl, pyridinyl, orpyrazinyl; wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl or cyclobutyl;

L² is —S(O)₂—; and

G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, or C₁-C₈-cycloalkyl.

In another embodiment, the compound is a compound of Formula (I)wherein: L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—; G¹ is —Ar¹-G^(a);R^(a), at each occurrence, is hydrogen; Ar¹ is pyrazin-2-yl; G^(a) iscyclopropyl; L² is —S(O)₂—; and G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, orC₁-C₈-cycloalkyl.

In further embodiments of each of the above embodiments, L¹ is—C(O)N(H)—. In further embodiments of each of the above embodiments, L¹is —N(H)C(O)—. In further embodiments of each of the above embodiments,L¹ is —O—.

(v) Additional Embodiments G²=Ar³

In one embodiment, the invention is directed to compounds of Formula (I)or Formula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—;

G¹ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹, —(CR^(a)R^(b))—Ar¹, —CH(Ar¹)₂,or —Ar¹-G^(a);

R^(a) and R^(b), at each occurrence, are each hydrogen;

R^(c) and R^(d) are each independently hydrogen or hydroxy;

Ar¹ is, at each occurrence, independently selected from the groupconsisting of phenyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and benzoxazolyl; wherein Ar¹ is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from the groupconsisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C⁴-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂—; and

G² is Ar³; and

Ar³ is dihydroindenyl, dihydrobenzofuranyl, orhexahydropyrrolo[1,2-a]-pyrazinyl; wherein the dihydroindenyl,dihydrobenzofuranyl, and hexahydropyrrolo[1,2-a]-pyrazinyl areunsubstituted or, in the case of compounds of Formula I, substitutedwith 1, 2, or 3 C₁-C₄-alkyl or oxo.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein:

R¹ is G¹-L¹-;

R² is hydrogen;

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

Ar¹ is, at each occurrence, independently phenyl, pyridin-2-yl, orpyrazin-2-yl; wherein Ar¹ is unsubstituted or substituted with 1 or 2substituents selected from the group consisting of halogen, C₁-C₄-alkyl,halomethyl, and halomethoxy;

G^(a) is cyclopropyl;

L² is —S(O)₂—;

G² is Ar³; and

Ar³ is dihydroindenyl, dihydrobenzofuranyl, orhexahydropyrrolo[1,2-a]-pyrazinyl; wherein the dihydroindenyl,dihydrobenzofuranyl, and hexahydropyrrolo[1,2-a]-pyrazinyl areunsubstituted or, in the case of compounds of Formula I, substitutedwith 1, 2, or 3 C₁-C₄-alkyl or oxo.

In another embodiment, the compound is a compound of Formula (I)wherein:

L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—;

G¹ is —Ar¹-G^(a);

R^(a), at each occurrence, is hydrogen;

Ar¹ is pyrazin-2-yl;

G^(a) is cyclopropyl;

L² is —S(O)₂—;

G² is Ar³; and

Ar³ is dihydroindenyl, dihydrobenzofuranyl, orhexahydropyrrolo[1,2-a]-pyrazinyl; wherein the dihydroindenyl,dihydrobenzofuranyl, and hexahydropyrrolo[1,2-a]-pyrazinyl areunsubstituted or, in the case of compounds of Formula I, substitutedwith 1, 2, or 3 C₁-C₄-alkyl or oxo.

In further embodiments of each of the above embodiments, L¹ is—C(O)N(H)—. In further embodiments of each of the above embodiments, L¹is —N(H)C(O)—. In further embodiments of each of the above embodiments,L¹ is —O—.

(vi) Additional Embodiments G¹=-Ar¹-G^(a) and G^(a)=Cyclopropyl

In one embodiment, the invention is directed to compounds of Formula (I)or Formula (I-A) wherein G¹ is —Ar¹-G^(a); Ar¹ is Ar¹ pyridinyl orpyrazinyl; and G^(a) is cyclopropyl.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein G¹ is —Ar¹-G^(a); Ar¹ is pyrazinyl; and G^(a) iscyclopropyl.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein G¹ is —Ar¹-G^(a); and —Ar¹-G^(a) is5-cyclopropylpyrazin-2-yl.

In further embodiments of each of the above embodiments, L¹ is—C(O)N(H)—. In further embodiments of each of the above embodiments, L¹is —N(H)C(O)—. In further embodiments of each of the above embodiments,L¹ is —O—.

(vii) Additional Embodiments G²=Ar² and Ar²=Phenyl or Pyridinyl

In one embodiment, the invention is directed to compounds of Formula (I)or Formula (I-A) wherein G² is Ar²; and Ar² is phenyl or pyridinyl;wherein Ar² is unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of halogen, cyano, C₁-C₄-alkyl,halomethyl, methoxy, and halomethoxy.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein G² is Ar²; and Ar² is phenyl; wherein Ar² isunsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of halogen, cyano, C₁-C₄-alkyl, halomethyl, methoxy,and halomethoxy.

In another embodiment, the compound is a compound of Formula (I) orFormula (I-A) wherein G² is Ar²; and Ar² is pyridinyl; wherein Ar² isunsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of halogen, cyano, C₁-C₄-alkyl, halomethyl, methoxy,and halomethoxy.

In further embodiments of each of the above embodiments, L¹ is—C(O)N(H)—. In further embodiments of each of the above embodiments, L¹is —N(H)C(O)—. In further embodiments of each of the above embodiments,L¹ is —O—.

(viii) Additional Embodiments Compounds of Formula (II)

In one embodiment, the invention is directed to compounds of Formula(II):

wherein:

R²¹ and R²² are independently selected from the group consisting ofhydrogen, C₁₋₃ alkyl, and cyclopropyl; and

one of R²³ and R²⁴ is hydrogen, and the other of R²³ and R²⁴ ishalomethyl.

In another embodiment, the invention is directed to compounds of Formula(II), wherein:

R²¹ and R²² are independently selected from the group consisting ofhydrogen, C₁₋₃ alkyl, and cyclopropyl; and

one of R²³ and R²⁴ is hydrogen, and the other of R²³ and R²⁴ istrifluoromethyl.

In another embodiment, the invention is directed to compounds of Formula(II-A):

wherein:

R²¹ and R²² are independently selected from the group consisting ofhydrogen, C₁₋₃ alkyl, and cyclopropyl; and

one of R²³ and R²⁴ is hydrogen, and the other of R²³ and R²⁴ ishalomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is hydrogen; R²² is selected from the group consisting ofhydrogen, C₁₋₃ alkyl, and cyclopropyl; R²³ is hydrogen; and R²⁴ ishalomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is hydrogen; R²² is selected from the group consisting ofhydrogen, C₁₋₃ alkyl, and cyclopropyl; R²³ is halomethyl; and R²⁴ ishydrogen.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of hydrogen, C₁₋₃alkyl, and cyclopropyl; R²² is hydrogen; R²³ is hydrogen; and R²⁴ ishalomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of hydrogen, C₁₋₃alkyl, and cyclopropyl; R²² is hydrogen; R²³ is halomethyl; and R²⁴ ishydrogen.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ and R²² are independently selected from the groupconsisting of hydrogen, isopropyl, and cyclopropyl; and one of R²³ andR²⁴ is hydrogen, and the other of R²³ and R²⁴ is halomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is hydrogen; R²² is selected from the group consisting ofhydrogen, isopropyl, and cyclopropyl; and one of R²³ and R²⁴ ishydrogen, and the other of R²³ and R²⁴ is halomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is C₁₋₃ alkyl; R²² is selected from the group consisting ofhydrogen, isopropyl, and cyclopropyl; and one of R²³ and R²⁴ ishydrogen, and the other of R²³ and R²⁴ is halomethyl.

In another embodiment, the compound is a compound of Formula (II-A), ora pharmaceutically acceptable salt thereof, wherein: R²¹ is cyclopropyl;R²² is selected from the group consisting of hydrogen, isopropyl, andcyclopropyl; and one of R²³ and R²⁴ is hydrogen, and the other of R²³and R²⁴ is halomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of hydrogenisopropyl, and cyclopropyl; R²² is hydrogen; and one of R²³ and R²⁴ ishydrogen, and the other of R²³ and R²⁴ is halomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of hydrogen,isopropyl, and cyclopropyl; R²² is C₁₋₃ alkyl; and one of R²³ and R²⁴ ishydrogen, and the other of R²³ and R²⁴ is halomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of hydrogen,isopropyl, and cyclopropyl; R²² is cyclopropyl; and one of R²³ and R²⁴is hydrogen, and the other of R²³ and R²⁴ is halomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ and R²² are independently selected from the groupconsisting of hydrogen, C₁₋₃ alkyl, and cyclopropyl; R²³ is hydrogen;and R²⁴ is halomethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ and R²² are independently selected from the groupconsisting of hydrogen, C₁₋₃ alkyl, and cyclopropyl; R²³ is halomethyl;and R²⁴ is hydrogen.

In another embodiment, the compound is a compound of Formula (II-A)wherein: one of R²¹ and R²² is hydrogen, and the other of R²¹ and R²² isselected from the group consisting of isopropyl and cyclopropyl; and oneof R²³ and R²⁴ is hydrogen, and the other of R²³ and R²⁴ istrifluoromethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is hydrogen; R²² is selected from the group consisting ofhydrogen, isopropyl, and cyclopropyl; R²³ is hydrogen; and R²⁴ istrifluoromethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is hydrogen; R²² is selected from the group consisting ofisopropyl and cyclopropyl; R²³ is hydrogen; and R²⁴ is trifluoromethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is hydrogen; R²² is selected from the group consisting ofhydrogen, isopropyl, and cyclopropyl; R²³ is trifluoromethyl; and R²⁴ ishydrogen.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is hydrogen; R²² is selected from the group consisting ofisopropyl and cyclopropyl; R²³ is trifluoromethyl; and R²⁴ is hydrogen.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of hydrogen,isopropyl and cyclopropyl; R²² is hydrogen; R²³ is hydrogen; and R²⁴ istrifluoromethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of isopropyl andcyclopropyl; R²² is hydrogen; R²³ is hydrogen; and R²⁴ istrifluoromethyl.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of hydrogen,isopropyl, and cyclopropyl; R²² is hydrogen; R²³ is trifluoromethyl; andR²⁴ is hydrogen.

In another embodiment, the compound is a compound of Formula (II-A)wherein: R²¹ is selected from the group consisting of isopropyl andcyclopropyl; R²² is hydrogen; R²³ is trifluoromethyl; and R²⁴ ishydrogen.

In another embodiment, the compound of Formula (II-A) is selected fromthe group consisting of:

-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-(pyrazin-2-yloxy)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;    and-   (7R,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine.

(ix) Additional Embodiments Z′ or Z″═C(O)

In one embodiment, the invention is directed to compounds of Formula(I):

wherein:

one of Z¹ and Z² is CH₂ and the other of Z¹ and Z² is C(O);

R¹ is G¹-L¹-;

L¹ is —C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—;

G¹ is C₁-C₈-alkyl, C₁-C₈-haloalkyl, Ar¹, —(CR^(a)R^(b))—Ar¹, —CH(Ar¹)₂,or —Ar¹-G^(a);

R^(a) and R^(b), at each occurrence, are each hydrogen;

R^(c) and R^(d) are each independently hydrogen or hydroxy;

Ar¹ is, at each occurrence, independently selected from the groupconsisting of phenyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and benzoxazolyl; wherein Ar¹ is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂— or —S(O)₂CH₂—;

G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-cycloalkyl, Ar², or Ar³;

Ar² is aryl or heteroaryl; wherein the Ar² aryl is selected from thegroup consisting of phenyl, naphthyl, and tetrahydronaphthylenyl; theAr² heteroaryl is selected from the group consisting of furyl, thienyl,pyrazolyl, and pyridinyl; and Ar² is unsubstituted or substituted with1, 2, 3, or 4 substituents selected from the group consisting ofhalogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u),—C(O)R^(u), —C(O)N(R^(u))(R^(v)), and -G^(b);

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl, wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl;

Ar³ is dihydroindenyl, dihydrobenzofuranyl, orhexahydropyrrolo[1,2-a]pyrazinyl; wherein the dihydroindenyl,dihydrobenzofuranyl, and hexahydropyrrolo[1,2-a]pyrazinyl areunsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl or oxo.

In one embodiment of the above compounds of Formula (I), Z¹ is CH₂; Z²is C(O); and L¹ is —O—. In another embodiment of the above compounds ofFormula (I), Z¹ is C(O); Z² is CH₂; and L¹ is —O—.

In one embodiment of the above compounds of Formula (I), —Ar¹-G^(a) is5-cyclopropylpyrazinyl.

In one embodiment of the above compounds of Formula (I), L² is —S(O)₂—;G² is Ar²; and Ar² is trifluoromethylphenyl or trifluoromethylpyridinyl.

In another embodiment, the compound is a compound of Formula (I)wherein:

one of Z¹ and Z² is CH₂ and the other of Z¹ and Z² is C(O);

L¹ is —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

Ar¹ is, at each occurrence, independently phenyl, pyridinyl, orpyrazinyl; wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3substituents selected from the group consisting of halogen, cyano,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl, cyclobutyl, or imidazolyl;

L² is —S(O)₂— or —S(O)₂CH₂—;

G² is Ar²;

Ar² is phenyl or pyridinyl; wherein Ar² is unsubstituted or substitutedwith 1, 2, or 3 substituents selected from the group consisting ofhalogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u),—C(O)R^(u), —C(O)N(R^(u))(R^(v)), and -G^(b);

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;and

R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl.

In another embodiment, the compound is a compound of Formula (I)wherein:

one of Z¹ and Z² is CH₂ and the other of Z¹ and Z² is C(O);

L¹ is —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

Ar¹ is, at each occurrence, independently phenyl, pyridinyl, orpyrazinyl;

wherein Ar¹ is unsubstituted or substituted with 1, 2, or 3 substituentsselected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy;

G^(a) is cyclopropyl or cyclobutyl;

L² is —S(O)₂—;

G² is Ar²;

Ar² is phenyl or pyridinyl; wherein Ar² is unsubstituted or substitutedwith 1, 2, or 3 substituents selected from the group consisting ofhalogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, and -G^(b); and

G^(b) is selected from the group consisting of cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl, wherein thecyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl.

In another embodiment, the compound is a compound of Formula (I)wherein:

one of Z¹ and Z² is CH₂ and the other of Z¹ and Z² is C(O);

L¹ is —C(O)N(H)—, —N(H)C(O)—, or —O—;

G¹ is Ar¹ or —Ar¹-G^(a);

Ar¹ is, at each occurrence, independently phenyl, pyridin-2-yl, orpyrazin-2-yl; wherein Ar¹ is unsubstituted or substituted with 1 or 2substituents selected from the group consisting of halogen, C₁-C₄-alkyl,halomethyl, and halomethoxy;

G^(a) is cyclopropyl;

L² is —S(O)₂—;

G² is Ar²; and

Ar² is phenyl or pyridinyl; wherein Ar² is unsubstituted or substitutedwith 1 or 2 substituents selected from the group consisting of halogen,cyano, C₁-C₄-alkyl, halomethyl, methoxy, and halomethoxy.

In another embodiment, the compound is a compound of Formula (I)wherein:

one of Z¹ and Z² is CH₂ and the other of Z¹ and Z² is C(O);

L¹ is —O—;

G¹ is —Ar¹-G^(a);

Ar¹ is pyrazin-2-yl;

G^(a) is cyclopropyl; and

Ar² is phenyl or pyridinyl; wherein Ar² is substituted with 1 or 2substituents selected from the group consisting of chloro, fluoro,trifluoromethyl, and trifluoromethoxy.

Specific embodiments of compounds contemplated as part of the inventioninclude, but are not limited to:

-   4-fluoro-N-[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   4-fluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-4-fluoro-benzamide;-   N-[(7S,8aS)-2-{[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]-4-fluorobenzamide;-   4-chloro-N-[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   4-chloro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   4-chloro-N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   4-chloro-N-[(7S,8aS)-2-{[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   4-chloro-N-[(7S,8aS)-2-{[2-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]-2,4-difluoro-benzamide;-   2,4-difluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   N-{(7S,8aS)-2-[(2,4-dichlorophenyl)sulfonyl]octahydropyrrolo[1,2-a]pyrazin-7-yl}-2,4-difluorobenzamide;-   N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-3,4-difluorobenzamide;-   3,4-difluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;-   (7S,8aS)-2-[(3,5-dichlorophenyl)sulfonyl]-N-[6-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[1,2-a]pyrazin-7-amine;-   (7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[6-(trifluoromethyl)-pyridin-2-yl]octahydropyrrolo[1,2-a]pyrazin-7-amine;-   (7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-(pyrazin-2-yloxy)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethoxy)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(difluoromethoxy)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(difluoromethoxy)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-fluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-fluoro-5-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-furylsulfonyl)-octahydropyrrolo-[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethoxy)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (8R*,8aS*)-8-[(5-chloropyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (8R*,8aR*)-8-[(5-chloropyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7S,8aS)—N-(diphenylmethyl)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide;-   (7S,8aS)—N-(diphenylmethyl)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide;-   (7S,8aS)—N-(diphenylmethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide;-   (7S,8aS)—N-(4,4,4-trifluorobutyl)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide;-   (7S,8aS)-7-[4-(trifluoromethoxy)phenoxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   (7S,8aS)-7-(4-tert-butylphenoxy)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   (7S,8aS)-7-[4-(1H-imidazol-1-yl)phenoxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-cyclopropylpyridazin-3-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-cyclopropylpyridazin-3-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(4-cyclopropylpyrimidin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(4-cyclopropylpyrimidin-2-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   1-(4-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}phenyl)ethanone;-   (7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-fluoro-5-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-fluoro-3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-chlorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(4-tert-butylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-tert-butyl-4-methoxyphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(morpholin-4-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(piperidin-1-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(pyrrolidin-1-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,4-difluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-5-(trifluoromethyl)benzonitrile;-   4-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-2-(trifluoromethyl)benzonitrile;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   2-chloro-5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;-   (7R,8aS)-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-2-{[6-(trifluoromethyl)-pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(5-tert-butyl-2-methoxyphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-methyl-2-thienyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(5-bromopyridin-3-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-cyclopropylpyridin-3-yl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(6-chloropyridin-3-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   5-{[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}-1,3-benzoxazole;-   (7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;-   2-methyl-6-{[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}-1,3-benzoxazole;-   (7S,8aS)-7-(4-fluoro-3-methylphenoxy)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-methylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-methylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-{[6-chloro-5-(trifluoromethyl)pyridin-3-yl]oxy}-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)-pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;-   6-{[(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}nicotinonitrile;-   5-{[(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}pyridine-2-carbonitrile;-   (7R,8aS)-7-[(6-bromopyridin-3-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-cyclopropylpyridin-3-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-bromopyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-bromopyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(6-cyclopropylpyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-bromo-1,3-thiazol-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropyl-1,3-thiazol-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3-difluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-fluoro-2-(piperidin-1-yl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(4-tert-butylbenzyl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-{[4-(trifluoromethoxy)benzyl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-{[4-(trifluoromethyl)benzyl]oxy}-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(1,1-difluoroethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclobutylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclobutylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-(biphenyl-3-ylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-isopropylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-methoxyphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-methoxy-3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   1-(3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}phenyl)ethanone;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(1,1-difluoroethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[3-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2,3-dihydro-1-benzofuran-5-yl-sulfonyl)octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[4-(trifluoromethyl)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-[(5-isopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4,5-trifluorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-fluoro-5-methylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,6-difluorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3,4-trifluorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(5-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-fluoro-4-methylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-difluorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-dimethylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[4-bromo-3-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-fluoro-2-methylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(4-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-difluorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-chloro-4-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(4-bromo-3-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(mesitylsulfonyl)-octahydropyrrolo-[1,2-a]pyrazine;-   (7R,8aS)-2-(biphenyl-4-ylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-bromophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[2,5-bis(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-fluoro-2-methylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dichloro-3-thienyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(5-chloro-2-thienyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(4-chlorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-fluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-fluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-methylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   2-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methoxyphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-dichlorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3-dichlorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(4-bromophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4-dichlorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dichlorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   4-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}benzonitrile;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,4-dichlorophenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(1-naphthylsulfonyl)-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-naphthylsulfonyl)-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-propylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}benzonitrile;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dimethoxyphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(3-chloro-4-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;-   5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-1-methyl-1,3-dihydro-2H-indol-2-one;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-ethyl-2-thienyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(1-ethyl-1H-pyrazol-4-yl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(2-cyclopropylpyrimidin-4-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(2-cyclopropylpyrimidin-4-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(5-tert-butyl-2-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methoxy-3-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-methoxy-5-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2,3-dihydro-1H-inden-5-yl-sulfonyl)octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4-dimethylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(1-methyl-1H-pyrazol-5-yl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-methyl-6-(trifluoromethyl)-pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(methoxymethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-methyl-3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-2-fluorobenzonitrile;-   2-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-4-methylbenzonitrile;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(1-isopropyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}-7-ethoxy-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,3,3-trifluoropropyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-(butylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-thienylsulfonyl)octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-(benzylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(isopropylsulfonyl)octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methylpyridin-2-yl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(6-methoxypyridin-3-yl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-N,N-dimethylbenzamide;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-fluoropyridin-3-yl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;-   2-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-4-(trifluoromethyl)benzonitrile;-   (7R,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-{[5-(prop-1-en-2-yl)-pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-[(5-isopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[6-(trifluoromethyl)-pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-2-yl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-{[5-(1-methylcyclopropyl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;-   7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (7R,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyaolo[1,2-a]pyrazin-6(2H)-one;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (8aS)-7-(3-fluorobenzyl)-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (8aS)-7-(3-fluorobenzyl)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (7S,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-2-{[3-(trifluoromethyl)-phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (7R,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-2-{[3-(trifluoromethyl)-phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)pyridin-2-yl]-oxy}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)benzyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4,4,4-trifluorobutyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one;-   (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one;-   (8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (8aS)-7-[3-(trifluoromethyl)benzyl]-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   (8aS)-7-[3-(trifluoromethyl)benzyl]-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   3-{[(8aS)-6-oxo-7-[3-(trifluoromethyl)benzyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;-   (7R,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)-pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;-   3-{[(7R,8aS)-7-{[5-(trifluoromethyl)pyridin-2-yl]oxy}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;-   (7R,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;-   3-{[(7R,8aS)-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;-   (7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;    and-   (7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)-pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine.

Compounds of the present application can exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The stereoisomers ofFormula (I) wherein R² is hydrogen include those depicted below asFormula (I-1), (I-2), (I-3), and (I-4):

The stereoisomers of Formula (I) wherein R¹ is hydrogen include thosedepicted below as Formula (I-4), (I-5), (I-6), (I-7), and (I-8):

In one embodiment, the invention is directed to compounds of Formula (I)having the configuration of Formula (I-2):

In another embodiment, the invention is directed to compounds of Formula(I) wherein Z′ and Z″ are CH₂, R² is hydrogen, and the compounds havethe configuration of Formula (I-2A):

On occasion, the relative stereochemistry of an enantiomeric pair isknown, however, the absolute configuration is not known. In thatcircumstance, the relative stereochemistry descriptor terms “R*” and“S*” are used. The terms “R*” and “S*” used herein are defined in Eliel,E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley &Sons, Inc.: New York, 1994; pp 119-120 and 1206. In a particularenantiomeric pair, the relative descriptors are reversed to indicatethat this pair of enantiomers is of unknown absolute stereochemistry.

The present application contemplates various stereoisomers and mixturesthereof and these are specifically included within the scope of thisapplication. Stereoisomers include enantiomers and diastereomers, andmixtures of enantiomers or diastereomers. Individual stereoisomers ofcompounds of the present application can be prepared synthetically fromcommercially available starting materials which contain asymmetric orchiral centers or by preparation of racemic mixtures followed byresolution which is well known to those of ordinary skill in the art.These methods of resolution are exemplified by (1) attachment of amixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Geometric isomers can exist in the present compounds. The inventioncontemplates the various geometric isomers and mixtures thereofresulting from the disposition of substituents around a carbon-carbondouble bond, a carbon-nitrogen double bond, a cycloalkyl group, or aheterocycle group. Substituents around a carbon-carbon double bond or acarbon-nitrogen bond are designated as being of Z or E configuration andsubstituents around a cycloalkyl or a heterocycle are designated asbeing of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed herein can exhibit the phenomenon of tautomerism.

Thus, the formulae drawings within this specification can represent onlyone of the possible tautomeric or stereoisomeric forms. It is to beunderstood that the invention encompasses any tautomeric orstereoisomeric form, and mixtures thereof, and is not to be limitedmerely to any one tautomeric or stereoisomeric form utilized within thenaming of the compounds or formulae drawings.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in Formula (I), but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes suitable for inclusion in the compoundsof the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine, and chlorine, such as, but not limited to ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Substitutionwith heavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Compounds incorporatingpositron-emitting isotopes are useful in medical imaging andpositron-emitting tomography (PET) studies for determining thedistribution of receptors. Suitable positron-emitting isotopes that canbe incorporated in compounds of Formula (I) are ¹¹C, ¹³N, ¹⁵O, and ¹⁸F.Isotopically-labeled compounds of Formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examplesusing appropriate isotopically-labeled reagent in place ofnon-isotopically-labeled reagent.

C. BIOLOGICAL DATA

Abbreviations which have been used in the descriptions of BiologicalData that follow are: EDTA for ethylenediaminetetraacetic acid; FBS forfetal bovine serum; FLIPR for fluorometric imaging plate reader; HBSSfor Hank's balanced salt solution; HEPES for4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; i.p. forintraperitoneal; MEM for minimum essential medium; MEM NEAA for minimumessential medium non-essential amino acid; p.o. for per orem (by mouth).

(i) In Vitro Assessment of Calcium Channel Activity Using FLIPR

IMR32 cells endogenously expressing human Ca_(v)2.2 were assayed forCa²⁺ influx using a no-wash calcium indicator dye (Calcium 4 dye:Molecular Probes) and FLIPR technology (Lubin, M L; et al. Assay andDrug Development Technologies, 2006, 4(6), 689-694). The IMR32 cellswere maintained in MEM media containing 10% (v/v) FBS, 1% (v/v)antibiotic/antimitotic, 1% (v/v) sodium pyruvate and 1% (v/v) MEM NEAA.Following dissociation in 0.05% (v/v) trypsin/EDTA, cells were seededinto black 1×96-well plates (Corning Cellbind) at a density of 1−1.2×10⁵cells/well and incubated in the maintenance media above for 48 hours at37° C. Immediately prior to performing the assay the media was removedand cells were loaded for 1.5 hours with 1× Calcium 4 dye prepared inHBSS (137 mM NaCl, 5.4 mM KCl, 0.25 mM Na₂HPO₄, 0.44 mM KH₂PO₄, 1.3 mMCaCl₂, 1 mM MgSO₄, 4.2 mM NaHCO₃) containing HEPES pH 7.4 at roomtemperature. After dye loading and a subsequent 60 minute pre-incubationwith compounds (full log dilutions from 10 μM to 0.1 nM) in the presenceof 1.3 mM CaCl₂ and 2 μM nifedipine to block endogenous L-type channels,the external Ca²⁺ concentration was increased to 5 mM CaCl₂ and thecells concomitantly depolarized with 80 mM KCl to assay channelactivity. To determine the IC₅₀ values, the percent inhibition of thecompound at each concentration was determined relative to the activityin the absence of inhibitor, and data was fitted using non-linearregression sigmoidal dose response curve analysis with GraphPad Prism®.Unless otherwise indicated (*), the reported values are average valuesfrom at least two runs (i.e., n≧2).

Example IC₅₀ (μM) 1 1.15 2 1.73 3 1.01 4 3.83 5 0.75 6 1.60 7 1.75 83.56 9 5.12 19 1.83 11 2.41 12 2.53 13 0.95 14 1.93 15 1.86 16 0.55 180.53 20 1.56 21 0.49 22 2.98 23 0.79 25 1.33 26 1.36 27 1.63 28 1.15 291.46 30 0.75 31 2.31 32 1.28 33 6.33 34 0.58 35 0.85 36 0.85 37 0.92 381.02 39 1.89 40 1.40 41 0.72 42 1.21 43 1.09 44 1.30 45 3.04 46 1.23 472.17 48 9.66 49 0.28 50 1.57 51 1.39 52 0.51 53 0.18 54 1.46 55 1.14 562.90 57 1.83 58 0.25 59 1.62 60 0.48 61 1.04 62 1.38* 63 1.38 64 0.81 651.65 66 0.46 67 1.80 68 1.04 69 0.46 70 6.97 71 2.35 72 3.76* 73 4.68 744.53 75 19.40 76 0.81 77 0.33 78 1.31 79 1.12 80 2.99 81 3.18 82 0.75 831.22 84 0.40 85 0.96 86 2.95 87 1.12 88 1.10 89 1.13 90 0.72 91 2.69 922.38 93 1.57 94 1.44 95 2.54 96 0.78 97 1.85 98 1.04 99 1.14 100 3.00101 0.93 102 1.90 103 2.29 104 1.66 105 3.99 106 1.06 108 4.36 109 1.61110 4.90* 111 2.90 112 5.89 113 0.94 114 6.81 115 1.96 116 2.57 117 0.47118 0.49 119 3.15 120 0.72 121 1.55 122 3.14 123 3.13* 124 3.05* 1251.51 126 3.46* 127 1.19* 128 4.14 129 0.89 130 1.30 131 3.94 132 2.40*133 1.93* 134 11.10* 135 1.75* 136 0.99 137 0.91 138 0.99 139 1.32140 >30 141 1.99* 142 3.03* 143 2.84 144 3.85* 145 3.12* 146 4.35 1476.15* 148 1.75* 149 0.43 150 1.41 151 1.34 152 1.15 153 5.50* 154 1.26*155 1.04 156 1.91 157 1.36 158 2.58* 159 4.68* 160 7.08* 161 1.71 1621.29 163 16.67 164 1.91 165 16.42 166 1.12 167 4.37 168 0.74 169 1.14170 2.64 171 5.74 172 1.21 173 >30 174 1.52 175 1.33 176 1.33 177 0.95178 3.02 179 1.64 180 0.50 181 >30 182 1.64 183 4.30 188 >30 189 >30 191ND 192 ND 193 ND 194 ND 195 ND 196 ND 197 ND 198 ND 199 ND 200 ND 2010.76 202 ND 203 0.13 204 0.38 205 0.28 206 1.52 207 0.88 208 1.56 2090.61 210 1.66 211 1.56 212 10.69 213 1.22 214 0.44 215 1.11 216 1.66 2170.78 218 16 219 >30 220 0.66 221 >30 222 1.25 223 0.127 224 0.353 2250.625 226 2.28 227 2.62 228 0.654 229 4.43 230 0.629 231 0.383 ND = notdetermined

(ii) In Vivo Assessment of Analgesic Effect Against Neuropathic Pain(Bennett Model)

Animals were prepared for testing, by use of a surgical procedure thatinduces neuropathic pain in one paw. IACUC guidelines for rodentsurvival surgery were followed. All surgical procedures were conductedon a clean, uncluttered surgical station. The area was wiped with a 70%ethanol solution before and after use. All instruments were sterilizedby either autoclave or chemical sterilant (such as 2% glutaraldehyde>10hours). Surgeons wore sterile gloves (for the initial procedure), cleanlab coat or scrubs, hairnet or cap, and a half-mask respirator (when notworking under a hood). Surgeons thoroughly washed their hands prior todonning sterile gloves. Gloves were disinfected in-between animals bycleansing with povidone iodine, chlorhexidine or 70% alcohol for atleast 30 seconds. If multiple surgeries were performed, the instrumentswere cleaned and sterilized between procedures with hot glass beads (>10seconds). To prevent thermal or chemical burns, the instruments werecooled by rinsing in sterile saline before use.

Male, Sprague Dawley® rats, 175-200 g were used for surgeries. Tominimize post-operative dehydration/maintain blood volume during thesurgery, warmed sterile saline or Lactate Ringers solution at 10-15mL/kg was administered subcutaneously immediately before or aftersurgery. This facilitated better renal function and presumablyanesthesia product excretion post surgery. For all surgical procedures,anesthesia was induced with 4-5% isoflurane. Anesthesia was maintainedduring surgery with 1-3% isoflurane. Following induction, the surgicalsite was carefully shaved and the exposed area was aseptically preparedwith povidone-iodine scrub solution and 70% ethanol 2-3 times.

Chronic constriction injury (CCl), a model of neuropathic pain, wasproduced by following the method of Bennett and Xie (Bennett, G, et al.Pain, 1988, 33, 87-107). After site sterilization and anestheticprocedures outline above were completed, a 1.5 cm incision was made atthe mid-thigh level to expose the biceps femoris and gluteoussuperficialis (right side), which were then separated by bluntdissection. The common sciatic nerve was exposed, isolated, and looselyligated by four 5-0 chromic gut ligatures with <1 mm spacing betweeneach. The surgical site was closed in layers—muscle was closed with 6.0absorbable sutures, and the skin closed with wound clips. Animals wereallowed to recover on a warming plate and were returned to their homecages when fully ambulatory. Animals were not be used for testing untilat least 10 days following surgery.

To measure mechanical sensitivity, tactile allodynia was measured usingcalibrated von Frey filaments (Stoelting, Wood Dale, Ill.) as describedby Chaplan et al. (Chaplan S., et al. J of Neuroscience Methods 1994,53, 55-63). Filament strengths used were: 0.4, 0.6, 1.0, 2, 4, 6, 8, and15 g. Rats were placed into inverted individual plastic containers(20×12.5×20 cm) on top of a suspended wire mesh grid, and acclimated tothe test chambers for at least 20 minutes. Filaments were appliedperpendicular to the mid-plantar paw surface with enough force to causeslight buckling and held in place for 6-8 seconds. Positive responsesincluded an abrupt withdrawal of the paw from the stimulus or flinchingbehavior immediately following removal of the stimulus. The maximumforce applied was 15 g. The 50% paw withdrawal threshold (PWT) wascalculated in grams (g) using the up-down method of Dixon (Dixon W. AnnRev Pharmacol Toxicol 1980, 20, 441-462). Only rats exhibiting increasedmechanical sensitivity were used (threshold responses below 5 g). Allcompounds were orally administered in at a dose of 10 mg/kg in 10%dimethyl sulfoxide/polyethylene glycol at a volume of 2.0 mL/kg, andmechanical allodynia was determined 60 minutes following compoundadministration. Data were reported as log g values and the percentage ofmaximum possible effect (% MPE) was calculated using log g values withthe formula:% MPE=(log [observed PWT in grams]−log [mean PWT vehicle])/(log [15]−log[mean PWT vehicle])*100

All statistical procedures were run on log g values.

Example % MPE 21 43 25 42 44 40 49 19 50 25 51 32 52 38 54 34 62 29 6437 67 5 86 0

The ability of the compounds of the present invention to reducenociceptive pain can be evaluated using conventional in vivo nociceptivepain models known in the art. Such models include, for example, thosedescribed in Pain (1996) 64:493-501; and Pain (2001) 93:69-76.

The ability of the compounds of the present invention to reduceinflammatory pain can be evaluated using conventional in vivonociceptive pain models known in the art. Such models include, forexample, those described in Pain (1999) 80:67-82.

D. METHODS OF USING THE COMPOUNDS

One embodiment of the present invention provides a method of treatingpain in a subject in need thereof. The method comprises administering tothe subject, including a mammal, such as a human, a therapeuticallysuitable amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. Conditions related to pain include, forexample, acute pain, chronic pain, neuropathic pain, nociceptive pain,allodynia, inflammatory pain, inflammatory hyperalgesia, post herpeticneuralgia, post-operative pain, post-stroke pain, neuropathies,neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury,rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, eyepain, visceral pain, cancer pain, dental pain, headache, migraine,carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvichypersensitivity, pelvic pain, menstrual pain. In one embodiment, thecondition related to pain is selected from the group consisting of acutepain, chronic pain, neuropathic pain, inflammatory pain, visceral pain,cancer pain, osteoarthritis pain, allodynia, fibromyalgia, sciatica,back pain, and headache pain including migraine, or combinationsthereof. Preferably, the method comprises administering to the mammal atherapeutically effective amount of any of the compounds as describedherein, or a pharmaceutically acceptable salt thereof.

Pain generally can be classified as acute or chronic. Acute pain beginssuddenly and is short-lived (usually twelve weeks or less). It isusually associated with a specific cause such as a specific injury andis often sharp and severe. It is the kind of pain that can occur afterspecific injuries resulting from surgery, dental work, a strain or asprain. Acute pain does not generally result in any persistentpsychological response. In contrast, chronic pain is long-term pain,typically persisting for more than three months and leading tosignificant psychological and emotional problems. Common examples ofchronic pain include neuropathic pain (e.g. painful diabetic neuropathy,postherpetic neuralgia), carpal tunnel syndrome, back pain, headache,cancer pain, arthritic pain and chronic post-surgical pain. In oneembodiment, the condition related to pain is chronic pain. In anotherembodiment, the condition related to pain is acute pain.

Pain also can be divided into a number of different subtypes accordingto differing pathophysiology, including neuropathic, nociceptive, andinflammatory pain. Some types of pain have multiple etiologies and canbe classified in more than one area, e.g., back pain and cancer painhave both nociceptive and neuropathic components. In one embodiment, thecondition related to pain is selected from the subtypes of neuropathicpain, nociceptive pain, and inflammatory pain.

In another embodiment, the condition related to pain is neuropathicpain. Neuropathic pain generally is defined as pain initiated or causedby a primary lesion or dysfunction in the nervous system and can result,for example, from trauma or disease. The term neuropathic painencompasses many conditions with diverse etiologies including peripheralneuropathy, diabetic neuropathy, post-herpetic neuralgia, trigeminalneuralgia, back pain, cancer neuropathy, HIV-neuropathy, phantom limbpain, carpal tunnel syndrome, central post-stroke pain, and painassociated with chronic alcoholism, hypothyroidism, uremia, multiplesclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamindeficiency.

In another embodiment, the condition related to pain is nociceptivepain. Nociceptive pain is induced by tissue injury or by intense stimuliwith the potential to cause injury. When a substantial injury occurs tobody tissue through trauma or disease, the characteristics of nociceptoractivation are altered and there is sensitization in the peripheryleading to a heightened sensation of pain in the subject. Moderate tosevere acute nociceptive pain is a prominent feature of pain fromcentral nervous system trauma, strains/sprains, burns, myocardialinfarction and acute pancreatitis, post-operative pain (pain followingany type of surgical procedure), post-traumatic pain, renal colic,cancer pain and back pain. Cancer pain can be chronic pain such as tumorrelated pain (e.g., bone pain, headache, facial pain or visceral pain)or pain associated with cancer therapy (e.g., post-chemotherapysyndrome, chronic postsurgical pain syndrome or post radiationsyndrome). Cancer pain can also occur in response to chemotherapy,immunotherapy, hormonal therapy or radiotherapy. Back pain can be due toherniated or ruptured intervertebral discs or abnormalities of thelumber facet joints, sacroiliac joints, paraspinal muscles or theposterior longitudinal ligament.

In another embodiment, the condition related to pain is inflammatorypain. A common type of inflammatory pain is arthritic pain arising fromrheumatoid disease (such as ankylosing spondylitis) or symptomaticosteoarthritis or degenerative joint disease. Another type ofinflammatory pain is visceral pain. Visceral pain is pain associatedwith the viscera, which encompass the organs of the abdominal cavityincluding the sex organs, spleen and part of the digestive system. Painassociated with the viscera can be divided into digestive visceral painand non-digestive visceral pain. Commonly encountered gastrointestinaldisorders that cause pain include functional bowel disorder andinflammatory bowel disease. These gastrointestinal disorders include awide range of disease states that are currently only moderatelycontrolled, including, with respect to functional bowel disorder,gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, andfunctional abdominal pain syndrome, and, in respect of inflammatorybowel disease, Crohn's disease, ileitis and ulcerative colitis, all ofwhich regularly produce visceral pain. Other types of visceral paininclude the pain associated with dysmenorrhea, cystitis and pancreatitisand pelvic pain.

In another embodiment, the condition related to pain results from amusculo-skeletal condition such as myalgia, fibromyalgia, spondylitis,sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism,dystrophinopathy, glycogenolysis, polymyositis and pyomyositis; heartand vascular pain, including pain caused by angina, myocardicalinfarction, mitral stenosis, pericarditis, Raynaud's phenomenon,scleredoma and skeletal muscle ischemia; head pain, such as migraine(including migraine with aura and migraine without aura), clusterheadache, tension-type headache mixed headache and headache associatedwith vascular disorders; and orofacial pain, including dental pain, oticpain, burning mouth syndrome and temporomandibular myofascial pain.

In certain embodiments, the method comprises administering to the mammala therapeutically effective amount of any of the compounds as describedherein, or a pharmaceutically acceptable salt thereof, in combinationwith one or more of the following: nonsteroidal anti-inflammatory drug(NSAID), opioid analgesic, barbiturate, benzodiazapine, histamineantagonist, sedative, skeletal muscle relaxant, transient receptorpotential ion channel antagonist, α-adrenergic, tricyclicantidepressant, anticonvulsant, tachykinin antagonist, muscarinicantagonist, cyclooxygenase-2 selective inhibitor, neuroleptic, vanilloidreceptor agonist, vanilloid receptor antagonist, β-adrenergic, localanesthetic, corticosteroid, 5-HT receptor agonist, 5-HT receptorantagonist, 5-HT_(2A) receptor antagonist, cholinergic analgesic, α₂δligand such as gabapentin or pregabalin, cannabinoid receptor ligand,metabotropic glutamate subtype 1 receptor antagonist, serotonin reuptakeinhibitor, norepinephrine reuptake inhibitor, dualserotonin-noradrenaline reuptake inhibitor, Rho kinase inhibitor,inducible nitric oxide synthase inhibitor, acetylcholinesteraseinhibitor, prostaglandin E₂ subtype 4 antagonist, leukotriene B4antagonist, 5-lipoxygenase inhibitor, sodium channel blocker, 5-HT3antagonist, N-methyl-D-aspartic acid receptor antagonist, andphosphodiesterase V inhibitor. In one embodiment, the method comprisesadministering to the subject a therapeutically effective amount of acompound described herein, or a pharmaceutically acceptable salt, withor without a pharmaceutically acceptable carrier, in combination with asecond therapeutic agent selected from the group consisting ofacetaminophen, opioid analgesics, NSAIDs, and combinations thereof.

Yet another embodiment of the present invention relates to a method forproviding a method for treating disorders of the central nervous systemincluding stroke, epilepsy, manic depression, bipolar disorders,depression, anxiety, schizophrenia, migraine, and psychoses; neuraldegenerative disorders including Alzheimer's disease, AIDS relateddementia, Parkinson's disease, neuropathy caused by head injury, anddementia caused by cerebrovascular disorders; disorders of the lowerurinary tract including overactive bladder, prostatis, prostadynia,interstitial cystitis, and benign prostatic hyperplasia; disorderscaused by psychogenic stress including bronchial asthma, unstableangina, and hypersensitive colon inflammation; cardiovascular disordersincluding hypertension, atherosclerosis, heart failure, and cardiacarrhythmias; drug addiction withdrawal symptoms, including ethanoladdiction withdrawal symptoms; skin disorders including pruritis andallergic dermatitis, inflammatory bowel disease; cancer; diabetes; andinfertility and sexual dysfunction in a mammal in need of suchtreatment. This method comprises administering to the mammal (includinghuman) a therapeutically effective amount of a compound of the inventionor a pharmaceutically acceptable salt thereof.

Calcium channel blockers have been associated with a slightly greaterdecreased risk of stroke compared to other types of antihypertensiveagents (Angeli, F.; et al. American Journal of Hypertension 2004, 17(9),817-822). The enhanced effect did not correlate with differences insystolic blood pressure and the mechanism of action remains unknown.However, calcium channel blockers have been associated with blockade ofcentral neuronal calcium influx and subsequent ischemic injury in tworodent models (Barone, F. C.; et al. Stroke 1995, 26, 1683-1690). Inanother model of global ischemia, a calcium channel blocker offeredneuroprotection although not permanently (Colbourne, F.; et al. Stroke1999, 30(3), 662-668). Additionally, diminished progression of carotidatherosclerosis has been observed with calcium channel blocker use(Zanchetti, A.; et al. Circulation 2002, 106, r47-r52).

An increase in intracellular calcium concentration has been correlatedwith seizure activity (Heinemann, U.; et al. Exp. Brain Res. 1977, 27,237-243). Several studies have indicated that calcium channel blockersproduce anticonvulsant activity (Vezzani, A.; et al. Neuropharmacology1988, 27(5), 451-458. Otoom, S.; et al. Fundamental & ClinicalPharmacology 2006, 20, 115-119).

Calcium channel blockers have been evaluated in the treatment of bipolardisorders and manic depression for decades. There are suggestions thatthe calcium channel subtype has influence on efficacy of these disorders(Gitlin, M. Molecular Psychiatry 2006, 11, 227-240. Levy, N. A.;Janicak, P. G Bipolar Disorders 2000, 2, 108-119).

Calcium channel blockers have also been associated with the treatment ofanxiety and depression (Saade, S.; et al. Pharmacology, Biochemistry andBehavior 2003, 74, 269-278).

Antischizophrenic drugs have been found to be calcium channelantagonists (Gould, R. J.; et al. Proc. Natl. Acad. Sci. USA 1983, 80,5122-5125). Other calcium channel blockers have been suggested for thetreatment of schizophrenia (Tort, A. B. L.; et al. Psychopharmacology2005, 177, 344-348). T-type calcium channels have been located in brainregions with relevance to schizophrenia and substance dependence(Talley, E. M.; et al. J Neurosci 1999, 19, 1895-1911).

Migraines are treated with calcium channel blockers (Arulmoshi, D. K.;et al. Vascular Pharmacology 2005, 43, 176-187. Gladstone, J. P.; et al.Expert Rev. Neurotherapeutics 2003, 3(6), 845-872).

Disorders of the lower urinary tract including overactive bladder,prostatis, prostadynia, interstitial cystitis, and benign prostatichyperplasia can be treated with calcium channel blockers (Fraser, M. O.;et al. US20050148587, 2005).

Ethanol withdrawal syndrome is decreased with calcium channel blockers(Little, H. J.; et al. Life Sciences 1986, 39, 2059-2065).

Dependence on nicotine has been decreased upon treatment with T-typecalcium channel blockers (Uslaner, J M; et al. Biological Psychiatry2010, 68(8), 712-718).

Several cardiac disorders are treated with calcium channel blockers.Atherosclerosis can be reduced by a decrease in free radical-mediateddamage as a result of influence on the biophysical properties ofmembranes (Mason, R. P.; et al. Biochemical Pharmacology 1998, 55,1843-1852). Hypertension and angina are both successfully treated withcalcium channel blockers (Croom, K. F.; et al. Drugs 2006, 66(4),497-528).

There is data suggesting that calcium channel blockers inhibit theproliferation of cancer cells (Gray, L. S.; et al. InternationalPublication No. WO200059882, 2000).

Calcium channels have been suggested as a target for the treatment ofdiabetes (Bhattacharjee, A.; et al. Endocrinology 1997, 138(9),3735-3740).

Ion channels including calcium channels play an important role in spermphysiology and fertilization (Darszon, A.; et al. Physiological Reviews1999, 79(2), 481-510).

Calcium channel blockers modulate inflammation (Bilici, D.; et al.Pharmacological Research 2001, 44(6), 527-531).

Increased calcium levels in neurones has been implicated in Alzheimer'sdisease. Two suggested mechanisms of increased calcium influx are thatβ-amyloid can form calcium permeable channels (Bhatia, R.; et al. FASEBJ. 2000, 14(9), 1233-1243) or a G-protein-coupled receptor can beactivated by β-amyloid (Lorton, D. Mech. Ageing Dev. 1997, 94(1-3),199-211).

Neurodegenerative diseases, including Parkinson's and Alzheimer'sdiseases can be modulated by calcium channel blockers (Rodnitzky, R. L.Drugs 1999, 57(6), 845-849. Vagnucci, A. H., Jr.; et al. The Lancet2003, 361(9357), 605-608. Veng, L. M.; et al. Molecular Brain Research2203, 110, 193-202. Geldenhuys, W. J.; et al. Bioorganic and MedicinalChemistry 2007, 15, 1525-1532. Cavalli, A.; et al. J. Med. Chem. 2008,51(3), 347-372).

Sleep disorders and absence epilepsy have been associated with calciumchannels (Shin, H.-S.; et al. Curr Opin Pharmacol, 2008, 8, 33-41).

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level can depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

Compounds of the invention can also be administered as a pharmaceuticalcomposition comprising the compounds of interest in combination with oneor more pharmaceutically acceptable carriers. The phrase“therapeutically effective amount” of the compound of the inventionmeans a sufficient amount of the compound to treat disorders, at areasonable benefit/risk ratio applicable to any medical treatment. Itcan be understood, however, that the total daily usage of the compoundsand compositions of the invention can be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective dose level for any particular patient candepend upon a variety of factors including the disorder being treatedand the severity of the disorder; activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factorswell-known in the medical arts. For example, it is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or other animal range from about 0.01 mg/kg body weight to about100 mg/kg body weight. More preferable doses can be in the range of fromabout 0.01 mg/kg body weight to about 30 mg/kg body weight. If desired,the effective daily dose can be divided into multiple doses for purposesof administration. Consequently, single dose compositions can containsuch amounts or submultiples thereof to make up the daily dose.

The present invention also is directed, in part, to a use of one or morecompounds and/or salts of the invention, and, optionally one or moreadditional therapeutic agents to prepare a medicament. In someembodiments, the medicament is for co-administration with one or moreadditional therapeutic agents. In some embodiments, the medicament isfor treating pain. In some embodiments, the medicament is for treatingneuropathic pain. In some embodiments, the medicament is for treatingnociceptive pain. In some embodiments, the medicament is for treatinginflammatory pain.

This invention also is directed, in part, to one or more compoundsand/or salts of the invention, and, optionally one or more additionaltherapeutic agents, for use as a medicament. In some embodiments, themedicament is for treating pain. In another embodiment, the medicamentis for treating neuropathic pain. In another embodiment, the medicamentis for treating nociceptive pain. In another embodiment, the medicamentis for treating inflammatory pain.

E. PHARMACEUTICAL COMPOSITIONS

The present invention further provides pharmaceutical compositions thatcomprise compounds of the present invention or a pharmaceuticallyacceptable salt or solvate thereof. The pharmaceutical compositionscomprise compounds of the present invention that can be formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers.

Another aspect of the present invention is a pharmaceutical compositioncomprising compounds of the invention, or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable carriers,alone or in combination with one or more nonsteroidal anti-inflammatorydrugs (NSAID), opioid analgesics, barbiturates, benzodiazepines,histamine antagonists, sedatives, skeletal muscle relaxants, transientreceptor potential ion channel antagonists, α-adrenergics, tricyclicantidepressants, anticonvulsants, tachykinin antagonists, muscarinicantagonists, cyclooxygenase-2 selective inhibitors, neuroleptics,vanilloid receptor agonists, vanilloid receptor antagonists,β-adrenergics, local anesthetics, corticosteroids, 5-HT receptoragonists, 5-HT receptor antagonists, 5-HT_(2A) receptor antagonists,cholinergic analgesics, α₂δ ligands such as gabapentin or pregabalin,cannabinoid receptor ligands, metabotropic glutamate subtype 1 receptorantagonists, serotonin reuptake inhibitors, norepinephrine reuptakeinhibitors, dual serotonin-noradrenaline reuptake inhibitors, Rho kinaseinhibitors, inducible nitric oxide synthase inhibitors,acetylcholinesterase inhibitors, prostaglandin E₂ subtype 4 antagonists,leukotriene B4 antagonists, 5-lipoxygenase inhibitors, sodium channelblockers, 5-HT3 antagonists, N-methyl-D-aspartic acid receptorantagonists, and phosphodiesterase V inhibitors.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It can also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, can depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound can be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form canalso comprise buffering agents.

Solid compositions of a similar type can also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theycan optionally contain opacifying agents and can also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms can containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, can contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundcan be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The saltscan be prepared in situ during the final isolation and purification ofthe compounds of the invention or separately by reacting a free basefunction with a suitable organic acid. Representative acid additionsalts include, but are not limited to acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium,triethylammonium, diethylammonium, ethylammonium and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The present invention also is directed, in part, to a kit comprising oneor more compounds and/or salts of the invention. The kit can optionallycontain one or more additional therapeutic agents and/or instructionsfor, for example, using the kit.

F. GENERAL SYNTHESIS

This invention is intended to encompass compounds of the invention whenprepared by synthetic processes or by metabolic processes. Preparationof the compounds by metabolic processes includes those occurring in thehuman or animal body (in vivo) or processes occurring in vitro.

This invention is directed, in part, to the synthetic processes forpreparing compounds of Formula I as shown in Schemes 1 through 14 andthe Examples below. This invention also is directed, in part, to novelintermediates that can be used to prepare the compounds of Formula I(and their salts) as shown in Schemes 1 through 14 and the Examplesbelow.

The compounds of the invention can be prepared by a variety of processeswell known for the preparation of compounds of this class. For example,the compounds of the invention wherein the groups Ar¹, G¹, G², Z′, Z″,R^(a) and R^(b), have the meanings as set forth in the Summary of theInvention section unless otherwise noted, can be synthesized as shown inSchemes 1-14.

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: APCI for atmospheric pressure chemicalionization; DMSO for dimethyl sulfoxide; ESI for electrosprayionization; LCMS for liquid chromatography-mass spectrometry; HPLC forhigh performance liquid chromatography; Ph for phenyl; and psi forpounds per square inch.

Compounds of Formula (I-4), wherein Z′, Z″, G¹ and G² are as defined inthe Summary of the Invention, can be prepared as illustrated inScheme 1. Compounds of Formula (I-1), wherein the primary amine can belocated at either the position of R¹ or R² in compounds of Formula (I)shown the Summary of the Invention and PG is a nitrogen protectinggroup, can be reacted with an acid chloride, G¹-C(O)—Cl, in the presenceof a base such as but not limited to sodium carbonate in a suitablesolvent at ambient or elevated temperature to afford compounds ofFormula (1-2). The protecting group can be removed from compounds ofFormula (1-2) under suitable conditions known to one skilled in the artto deliver compounds of Formula (1-3). For example, if the protectinggroup is a benzyl group, it can be removed by catalytic hydrogenation inthe presence of a palladium or palladium hydroxide catalyst.Alternatively, if the protecting group is ten-butoxycarbonyl, exposureto acids such as hydrochloric acid or trifluoroacetic acid will removethe protecting group. Compounds of Formula (1-3) can be reacted withsulfonyl chlorides, G²-S(O)₂—Cl, in the presence of a base in a suitablesolvent at or near room temperature to give compounds of Formula (1-4)which are representative of compounds of Formula (I).

As shown in Scheme 2, compounds of Formula (1-1) can be transformed tocompounds of Formula (2-4) which are representative of compounds ofFormula (I). Compounds of Formula (1-1) can be reacted with compounds ofFormula (2-1) in the presence of a base such as but not limited tosodium carbonate in a solvent such as heated dimethyl sulfoxide to givecompounds of Formula (2-2). In compounds of Formula (2-1), Hal¹ isfluorine, chlorine, bromine or iodine. Also in compounds of Formula(2-1) one or none of Z¹, Z², Z³ and Z⁴ can be nitrogen and the others ofZ¹, Z², Z³ and Z⁴ are CR′, wherein R′ is either hydrogen or thesubstituents described for Ar¹ in the Summary of the Invention.Compounds of Formula (2-3) can be deprotected to give compounds ofFormula (2-3) and subsequently sulfonylated to give compounds of Formula(2-4) as described in Scheme 1.

As shown in Scheme 3, compounds of Formula (3-1) can be reacted withcompounds of Formula (2-1) in the presence of a base in an optionallyheated solvent to give compounds of Formula (3-2). The protecting groupcan be removed from compounds of Formula (3-2) under suitable conditionsknown to one skilled in the art to deliver compounds of Formula (3-3).Compounds of Formula (3-3) can be reacted with sulfonyl chlorides,G²-S(O)₂—Cl, in the presence of a base in a suitable solvent at or nearroom temperature to give compounds of Formula (3-4) which arerepresentative of compounds of Formula (I).

Scheme 4 depicts the alternative transformation of compounds of Formula(3-1) to compounds of Formula (3-4) as well as the sequence to delivercompounds of Formula (4-3). Compounds of Formula (3-1) can bedeprotected to give compounds of Formula (4-1). Compounds of Formula(4-1) can be sulfonylated with sulfonyl chlorides, G²-S(O)₂—Cl, in thepresence of a base in a suitable solvent at or near room temperature togive compounds of Formula (4-2). Compounds of Formula (4-2) can bereacted with compounds of Formula (2-1) in the presence of a base suchas potassium tert-butoxide in a suitable solvent to give compounds ofFormula (3-4). Compounds of Formula (4-2) can be reacted with compounds,Ar¹—OH, wherein Ar¹ is as defined in the Summary of the Invention, underMitsunobu reaction conditions to give compounds of Formula (4-3).Compounds of Formula (3-4) and compounds of Formula (4-3) arerepresentative of compounds of Formula (I).

As shown in Scheme 5, compounds of Formula (5-1) can supply compounds ofFormula (5-4) which are representative of compounds of Formula (I).Compounds of Formula (5-1) can be coupled with amines, G¹-N(R^(a))H, togive compounds of Formula (5-2). Examples of conditions known togenerate amides from a mixture of a carboxylic acid and an amine includebut are not limited to adding a coupling reagent such as but not limitedto N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC or EDCI),1,3-dicyclohexyl-carbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinicchloride (BOPCl),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), and2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HBTU). The coupling reagents can be added as asolid, a solution or as the reagent bound to a solid support resin. Inaddition to the coupling reagents, auxiliary-coupling reagents canfacilitate the coupling reaction. Auxiliary coupling reagents that areoften used in the coupling reactions include but are not limited to(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and1-hydroxybenzotriazole (HOBT). The reaction can be carried outoptionally in the presence of a base such as triethylamine ordiisopropylethylamine. The coupling reaction can be carried out insolvents such as but not limited to tetrahydrofuran,N,N-dimethylformamide, dichloromethane, and ethyl acetate. The reactioncan be conducted at ambient or elevated temperatures.

Alternatively, compounds of Formula (5-1) can be converted to thecorresponding carboxylic acid chloride and then reacted with amines,G¹-N(R^(a))H, to give compounds of Formula (5-2) optionally in thepresence of a base in a suitable solvent.

Compounds of Formula (5-2) can be deprotected to give compounds ofFormula (5-3) and then sulfonylated to give compounds of Formula (5-4)as described in Scheme 1.

As shown in Scheme 6, sulfonyl chlorides of Formula (6-3) can beprepared from compounds of Formula (6-1), wherein one or none of Z⁵, Z⁶,Z⁷ and Z⁸ can be nitrogen and the others of Z⁵, Z⁶, Z⁷ and Z⁸ are CR″,wherein R″ is either hydrogen or the substituents described for Ar² inthe Summary of the Invention. Compounds of Formula (6-1) can be treatedwith benzyl mercaptan in the presence of a base such as potassiumtert-butoxide in an optionally heated solvent such asN,N-dimethylformamide to give compounds of Formula (6-2). Compounds ofFormula (6-2) can then be reacted either with N-chlorosuccinimide orchlorine gas in a mixture of water and acetic acid to give compounds ofFormula (6-3). Compounds of Formula (6-3) are compounds of formulaG²-S(O)₂—Cl and can be used in reactions described in Schemes 1-5, 12and 13.

As shown in Scheme 7, compounds of Formula (7-2) can be prepared fromcompounds of Formula (4-2). Compounds of Formula (4-2) can be treatedwith a base such as potassium t-butoxide in a solvent such as dimethylsulfoxide in the presence of compounds of Formula (7-1), wherein R′ iseither hydrogen or the substituents described for Ar¹ in the Summary ofthe Invention, to give compounds of Formula (7-2). Compounds of Formula(7-2) are representative of compounds of Formula (I).

As shown in Scheme 8, compounds of Formula (8-2) can be prepared fromcompounds of Formula (8-1). Compounds of Formula (8-1), wherein Het1 isa 5- or 6-membered heteroaryl that contains one nitrogen atom andoptionally a second heteroatom, can be reacted with cyclopropylzinc(II)bromide in the presence of a palladium catalyst such as[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride to give compounds of Formula (8-2). Compounds of Formula(8-2) are representative a compounds of Formula (I).

As shown in Scheme 9, compounds of Formula (9-1), Formula (9-2) andFormula (9-3) can be prepared from compounds of Formula (4-2). Compoundsof Formula (4-2) can be reacted with Ar¹C(R^(a))R^(b))-LG; wherein Ar¹,R^(a) and R^(b) are as described in the Summary, and LG is a suitableleaving group such as bromine, chlorine, iodine, or a sulfonate; in thepresence of a base to give compounds of Formula (9-1). Similarly,compounds of Formula (4-2) can be reacted with (Ar¹)₂CH-LG in thepresence of a base to give compounds of Formula (9-2). Compounds ofFormula (4-2) can also be reacted with alkyl-LG or haloalkyl-LG in thepresence of a base to give compounds of Formula (9-3). Compounds ofFormula (9-1), Formula (9-2), and Formula (9-3) are representative ofcompounds of Formula (I).

As shown in Scheme 10, compounds of Formula (10-2) can be prepared fromcompounds of Formula (10-1). Compounds of Formula (10-1), wherein Ar¹ issubstituted with a C₂-C₄-alkenyl, can be reduced with hydrogen in thepresence of a catalyst such as palladium on carbon, palladium hydroxideon carbon, or Raney® nickel to give compounds of Formula (10-2).Compounds of Formula (10-2) are representative a compounds of Formula(I).

As shown in Scheme 11, compounds of Formula (11-3) can be prepared fromcompounds of Formula (11-1). Compounds of Formula (11-1) can bedeprotonated with a base such as lithium bis(trimethylsilyl)amide andthen treated with 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine to givecompounds of Formula (11-2). Compounds of Formula (11-2) can be reactedin the sequences described in Schemes 3, 4, 7 and 9 to give compounds ofFormula (11-3). Compounds of Formula (11-3) are representative ofcompounds of Formula (I).

As shown in Scheme 12, compounds of Formula (12-2) and Formula (12-4)can be prepared from compounds of Formula (11-1). Compounds of Formula(11-1) can be deprotonated and then treated with Ar¹C(R^(a))(R^(b))-LGto give compounds of Formula (12-1). The protecting group of compoundsof Formula (12-1) can be removed under suitable conditions known to oneskilled in the art, and then the intermediate can be reacted withsulfonyl chlorides, G²-S(O)₂—Cl, in the presence of a base in a suitablesolvent at or near room temperature to give compounds of Formula (12-2)which are representative of compounds of Formula (I). Compounds ofFormula (11-1) can also be deprotonated and then treated with aldehydes,Ar¹CHO, to give compounds of Formula (12-3). The protecting group ofcompounds of Formula (12-3) can be removed under suitable conditionsknown to one skilled in the art, and then the intermediate can bereacted with sulfonyl chlorides, G²-S(O)₂—Cl, in the presence of a basein a suitable solvent at or near room temperature to give compounds ofFormula (12-4) which are representative of compounds of Formula (I).

As shown in Scheme 13, compounds of Formula (11-3) can be prepared fromcompounds of Formula (13-1). Compounds of Formula (13-1) can be reactedwith sulfonyl chlorides, G²-S(O)₂—Cl, in the presence of a base in asuitable solvent at or near room temperature to give sulfonylatedcompounds and then subsequently can be deprotonated and then treatedwith 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine to give compounds ofFormula (13-2). Compounds of Formula (13-2) can be reacted in thesequences described in Schemes 4, 7 and 9 to give compounds of Formula(11-3). Compounds of Formula (11-3) are representative of compounds ofFormula (I).

As shown in Scheme 14, compounds of Formula (14-8) can be prepared fromcompounds of Formula (14-1). Compounds of Formula (14-1), wherein PG isa nitrogen protecting group, can be converted to compounds of Formula(14-2) by selective activation of the primary alcohol and subsequentdisplacement with azide. Compounds of Formula (14-2) can then beconverted to compounds of Formula (14-3) by first introducing a G¹group, wherein G¹ is as defined in the Summary, using the methodologiespreviously described in Schemes 3, 4, 7, or 9; and second, reducing theazide to the corresponding amine Compounds of Formula (14-3) can bereacted with compounds of Formula (14-4), wherein LG is a suitableleaving group such as bromine, chlorine, iodine, or a sulfonate, to givecompounds of Formula (14-5). Compounds of Formula (14-5) can be treatedwith G²SO₂Cl optionally in the presence of a base to give compounds ofFormula (14-6). After removal of the protecting group and cyclization ofthat intermediate, compounds of Formula (14-6) are transformed tocompounds of Formula (14-8). Alternatively, removal of the protectinggroup on compounds of Formula (14-5) and cyclization of thatintermediate gives compounds of Formula (14-7). Compounds of Formula(14-7) can be treated with G²SO₂Cl optionally in the presence of a baseto give compounds of Formula (14-8). Compounds of Formula (14-8) arerepresentative of compounds of Formula (I).

Optimum reaction conditions and reaction times for each individual stepcan vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions can be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions can be worked up in the conventionalmanner, e.g. by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or can beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that can not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which canbe found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention can be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, can be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it can be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it can be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

It can be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

G. EXAMPLES Example 14-fluoro-N-[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamideExample 1A tert-butyl(7S,8aS)-7-[(4-fluorobenzoyl)amino]hexahydropyrrolo[1,2-a]-pyrazine-2(1H)-carboxylate

To (7S,8aS)-tert-butyl7-aminohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.241 g, 1mmol) in dichloromethane (6 mL) was added sodium carbonate (0.127 g, 1.2mmol) and 4-fluorobenzoyl chloride (0.174 g, 1.1 mmol). The mixture wasstirred at room temperature for 4 hours. The mixture was concentrated.The residue was purified by chromatography on silica gel (ethyl acetate,then ethyl acetate/methanol=10:1) to give the title compound. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.40 (m, 1H), 1.47 (s, 9H), 1.63 (m, 2H),2.05-2.20 (m, 2H), 2.50-2.65 (m, 2H), 3.00 (m, 2H), 4.20 (m, 2H), 4.70(m, 1H), 6.68 (m, 1H), 7.10 (m, 2H), 7.80 (m, 2H); MS (ESI) m/z 364(M+H)⁺.

Example 1B4-fluoro-N-[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

To a solution of Example 1A (200 mg, 0.55 mmol) in dichloromethane (2mL) was added trifluoroacetic acid (1 mL). The mixture was stirred atroom temperature for 3 hours, and then concentrated to give a crudeintermediate where the t-butoxycarbonyl protective group has beenremoved from the starting material. To the above crude intermediate(0.12 mmol) in dichloromethane (2 mL) and N,N-dimethylformamide (0.5 mL)was added sodium carbonate (51 mg, 0.48 mmol), and3-(trifluoromethyl)benzene-1-sulfonyl chloride (53 mg, 0.216 mol) indichloromethane (0.5 mL). The mixture was stirred at room temperaturefor 3 hours, and then concentrated. The residue was purified bychromatography on silica gel (ethyl acetate, then ethylacetate/methanol=50:1) to give the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.41 (m, 1H), 2.10 (m, 3H), 2.30 (m, 1H), 2.40 (m, 2H),2.84 (m, 1H), 3.00 (m, 1H), 3.68 (m, 1H), 3.82 (m, 1H), 4.32 (m, 1H),7.23 (m, 2H), 7.90 (m, 3H), 8.00 (s, 1H), 8.16 (m, 2H), 8.38 (m, 1H); MS(ESI) m/z 472 (M+H)⁺.

Example 24-fluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

The title compound was prepared according to the procedure described inExample 1 substituting 4-(trifluoromethyl)benzene-1-sulfonyl chloridefor 3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.41 (m, 1H), 2.05-2.20 (m, 3H), 2.30 (m, 1H), 2.40 (m,2H), 2.84 (m, 1H), 3.00 (m, 1H), 3.62 (m, 1H), 3.80 (m, 1H), 4.34 (m,1H), 7.23 (m, 2H), 7.88 (m, 2H), 8.00 (d, 2H, J=7 Hz), 8.08 (d, 2H, J=7Hz), 8.39 (m, 1H); MS (ESI) m/z 472 (M+H)⁺.

Example 3N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-4-fluorobenzamide

The title compound was prepared according to the procedure described inExample 1 substituting 2-chloro-4-(trifluoromethyl)benzene-1-sulfonylchloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.42 (m, 1H), 2.00-2.10 (m, 2H), 2.27 (m, 1H), 2.42(m, 1H), 2.64 (m, 1H), 2.90-3.00 (m, 3H), 3.69 (m, 1H), 3.83 (m, 1H),4.35 (m, 1H), 7.25 (m, 2H), 7.92 (m, 3H), 8.20 (m, 2H), 8.42 (m, 1H); MS(ESI) m/z 506 (M+H)⁺.

Example 4N-[(7S,8aS)-2-{[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-4-fluorobenzamide

The title compound was prepared according to the procedure described inExample 1 substituting 2-chloro-5-(trifluoromethyl)benzene-1-sulfonylchloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.45 (m, 1H), 2.00-2.10 (m, 2H), 2.28 (m, 1H), 2.40(m, 1H), 2.62 (m, 1H), 2.88-3.00 (m, 3H), 3.71 (m, 1H), 3.85 (m, 1H),4.34 (m, 1H), 7.24 (m, 2H), 7.90 (m, 2H), 7.99 (m, 1H), 8.10 (m, 1H),8.20 (s, 1H), 8.45 (m, 1H); MS (ESI) m/z 506 (M+H)⁺.

Example 54-chloro-N-[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 4-chlorobenzoyl chloride for 4-fluorobenzoylchloride followed by the procedure described in Example 1B. ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.41 (m, 1H), 2.10 (m, 3H), 2.28 (m, 1H), 2.38 (m,2H), 2.85 (m, 1H), 2.99 (m, 1H), 3.68 (m, 1H), 3.82 (m, 1H), 4.32 (m,1H), 7.46 (m, 2H), 7.82 (m, 2H), 7.92 (m, 1H), 8.00 (s, 1H), 8.15 (m,2H), 8.42 (m, 1H); MS (ESI) m/z 488 (M+H)⁺.

Example 64-chloro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 4-chlorobenzoyl chloride for 4-fluorobenzoylchloride followed by the procedure described in Example 1B, substituting4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.41 (m, 1H), 2.07-2.20 (m, 3H), 2.29 (m, 1H), 2.39 (m,2H), 2.84 (m, 1H), 3.00 (m, 1H), 3.63 (m, 1H), 3.80 (m, 1H), 4.34 (m,1H), 7.48 (d, 2H, J=7 Hz), 7.82 (d, 2H, J=7 Hz), 8.00 (d, 2H, J=7 Hz),8.07 (d, 2H, J=7 Hz), 8.42 (m, 1H); MS (ESI) m/z 488 (M+H)⁺.

Example 74-chloro-N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 4-chlorobenzoyl chloride for 4-fluorobenzoylchloride followed by the procedure described in Example 1B, substituting2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.44 (m, 1H), 2.00-2.12 (m, 2H), 2.29 (m, 1H), 2.41 (m,1H), 2.63 (m, 1H), 2.86-3.00 (m, 3H), 3.71 (m, 1H), 3.83 (m, 1H), 4.34(m, 1H), 7.51 (d, 2H, J=7 Hz), 7.83 (d, 2H, J=7 Hz), 7.98 (d, 1H, J=7Hz), 8.21 (m, 2H), 8.55 (m, 1H); MS (ESI) m/z 522 (M+H)⁺.

Example 84-chloro-N-[(7S,8aS)-2-{[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 4-chlorobenzoyl chloride for 4-fluorobenzoylchloride followed by the procedure described in Example 1B, substituting4-fluoro-2-(trifluoromethyl)-benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.46 (m, 1H), 2.00-2.18 (m, 2H), 2.28 (m, 1H), 2.41 (m,1H), 2.57 (m, 1H), 2.79 (m, 1H), 2.96 (m, 1H), 3.02 (m, 1H), 3.68 (m,1H), 3.81 (m, 1H), 4.35 (m, 1H), 7.52 (d, 2H, J=7 Hz), 7.78 (m, 1H),7.84 (d, 2H, J=7 Hz), 7.99 (d, 1H, J=7 Hz), 8.19 (m, 1H), 8.54 (m, 1H);MS (ESI) m/z 506 (M+H)⁺.

Example 94-chloro-N-[(7S,8aS)-2-{[2-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 4-chlorobenzoyl chloride for 4-fluorobenzoylchloride followed by the procedure described in Example 1B, substituting2-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.45 (m, 1H), 2.02-2.18 (m, 2H), 2.28 (m, 1H), 2.41 (m,1H), 2.57 (m, 1H), 2.79 (m, 1H), 2.94 (m, 1H), 2.99 (m, 1H), 3.68 (m,1H), 3.82 (m, 1H), 4.36 (m, 1H), 7.52 (d, 2H, J=7 Hz), 7.84 (d, 2H, J=7Hz), 7.92 (m, 1H), 8.02 (m, 1H), 8.09 (m, 1H), 8.52 (m, 1H); MS (ESI)m/z 488 (M+H)⁺.

Example 10N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-2,4-difluorobenzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 2,4-difluorobenzoyl chloride for4-fluorobenzoyl chloride followed by the procedure described in Example1B, substituting 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloridefor 3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.37 (m, 1H), 2.00-2.12 (m, 2H), 2.29 (m, 1H), 2.41 (m,1H), 2.62 (m, 1H), 2.84-3.00 (m, 3H), 3.71 (m, 1H), 3.83 (m, 1H), 4.34(m, 1H), 7.15 (m, 1H), 7.31 (m, 1H), 7.60 (m, 1H), 7.97 (m, 1H), 8.20(m, 2H), 8.43 (m, 1H); MS (ESI) m/z 524 (M+H)⁺.

Example 112,4-difluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 2,4-difluorobenzoyl chloride for4-fluorobenzoyl chloride followed by the procedure described in Example1B, substituting 4-(trifluoromethyl)-benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.35 (m, 1H), 2.03-2.17 (m, 3H), 2.29-2.39 (m, 3H), 2.62(m, 1H), 2.98 (m, 1H), 3.68 (m, 1H), 3.80 (m, 1H), 4.30 (m, 1H), 7.10(m, 1H), 7.30 (m, 1H), 7.58 (m, 1H), 7.97-8.02 (m, 4H), 8.38 (m, 1H); MS(ESI) m/z 490 (M+H)⁺.

Example 12N-{(7S,8aS)-2-[(2,4-dichlorophenyl)sulfonyl]octahydropyrrolo[1,2-a]pyrazin-7-yl}-2,4-difluorobenzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 2,4-difluorobenzoyl chloride for4-fluorobenzoyl chloride followed by the procedure described in Example1B, substituting 2,4-dichlorobenzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.37 (m, 1H), 2.00-2.10 (m, 2H), 2.29 (m, 1H), 2.40 (m,1H), 2.58 (m, 1H), 2.82 (m, 1H), 2.90 (m, 1H), 2.99 (m, 1H), 3.64 (m,1H), 3.80 (m, 1H), 4.30 (m, 1H), 7.12 (m, 1H), 7.30 (m, 1H), 7.60-7.64(m, 2H), 7.91 (s, 1H), 7.99 (m, 1H), 8.42 (m, 1H); MS (ESI) m/z 490(M+H)⁺.

Example 13N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-3,4-difluorobenzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 3,4-difluorobenzoyl chloride for4-fluorobenzoyl chloride followed by the procedure described in Example1B, substituting 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloridefor 3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.42 (m, 1H), 2.00-2.15 (m, 2H), 2.28 (m, 1H), 2.41 (m,1H), 2.64 (m, 1H), 2.86-3.00 (m, 3H), 3.71 (m, 1H), 3.83 (m, 1H), 4.35(m, 1H), 7.54 (m, 1H), 7.75 (m, 1H), 7.90-7.97 (m, 2H), 8.20 (m, 2H),8.58 (m, 1H); MS (ESI) m/z 524 (M+H)⁺.

Example 143,4-difluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide

The title compound was prepared according to the procedure described inExample 1A, substituting 3,4-difluorobenzoyl chloride for4-fluorobenzoyl chloride followed by the procedure described in Example1B, substituting 4-(trifluoromethyl)-benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.40 (m, 1H), 2.05-2.20 (m, 3H), 2.25-2.41 (m, 3H), 2.84(m, 1H), 3.00 (m, 1H), 3.68 (m, 1H), 3.81 (m, 1H), 4.31 (m, 1H), 7.50(m, 1H), 7.70 (m, 1H), 7.91 (m, 1H), 8.02 (m, 4H), 8.48 (m, 1H); MS(ESI) m/z 490 (M+H)⁺.

Example 15(7S,8aS)-2-[(3,5-dichlorophenyl)sulfonyl]-N-[6-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[1,2-a]pyrazin-7-amineExample 15A tert-butyl(7S,8aS)-7-{[6-(trifluoromethyl)pyridin-2-yl]amino}hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To (7S,8aS)-tert-butyl7-aminohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (310 mg, 1.29mmol) and sodium carbonate (0.26 g, 2.5 mmol) in dimethyl sulfoxide (1mL) was added 2-chloro-6-(trifluoromethyl)pyridine (0.35 g, 1.93 mmol).The mixture was stirred at 100° C. for 3 days and then concentrated. Theresidue was purified by chromatography on silica gel (100% ethylacetate) to provide the title compound. MS (ESI) m/z 387 (M+H)⁺.

Example 15B(7S,8aS)—N-(6-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-amine

To Example 15A (0.43 g, 1.113 mmol) in methanol (5 mL) was added 4 Nhydrochloric acid in dioxane (5 mL). The mixture was heated at 80° C.for 1 hour and then concentrated to provide the title compound as thehydrochloric acid salt. MS (ESI) m/z 287 (M+H)⁺.

Example 15C(7S,8aS)-2-[(3,5-dichlorophenyl)sulfonyl]-N-[6-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[1,2-a]pyrazin-7-amine

To a solution of Example 15B (70 mg, 0.217 mmol) in triethylamine (40mg, 0.4 mmol) and dichloromethane (1 mL) was added a solution of3,5-dichlorobenzene-1-sulfonyl chloride (53 mg, 0.217 mmol) indichloromethane (1 mL). The mixture was stirred at room temperature for18 hours and then concentrated. The residue was purified bychromatography on silica gel (ethyl acetate/methanol=20:1) to give thetitle compound. ¹NMR (500 MHz, DMSO-d₆) δ ppm 1.23 (m, 2H), 2.14 (m,2H), 2.38 (m, 3H), 2.78 (m, 1H), 2.96 (m, 1H), 3.64 (m, 1H), 3.81 (m,1H), 4.20 (m, 1H), 6.65 (d, 1H, J=7 Hz), 6.86 (d, 1H, J=7 Hz), 7.15 (d,1H, J=7 Hz), 7.52 (t, 1H, J=7 Hz), 7.78 (s, 2H), 8.04 (m, 1H); MS (ESI)m/z 496 (M+H)⁺.

Example 16(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[6-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[1,2-a]pyrazin-7-amine

The title compound was prepared according to the procedure described inExample 15C, substituting 2-chloro-4-(trifluoromethyl)benzene-1-sulfonylchloride for 3,5-dichlorobenzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.23 (m, 2H), 2.14 (m, 2H), 2.38 (m, 3H), 2.78 (m, 1H),2.96 (m, 1H), 3.64 (M, 1H), 3.81 (m, 1H), 4.20 (m, 1H), 6.65 (d, 1H, J=7Hz), 6.86 (d, 1H, J=7 Hz), 7.21 (d, 1H, J=7 Hz), 7.52 (t, 1H, J=7 Hz),7.94 (d, 1H, J=7 Hz), 8.18 (m, 2H); MS (ESI) m/z 529 (M+H)⁺.

Example 17(7S,8aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]-pyrazin-7-olExample 17A (2R,4S)-methyl 4-hydroxypyrrolidine-2-carboxylatehydrochloride

To a suspension of trans-4-hydroxy-D-proline hydrochloride (150 g, 0.89mol, 1 equivalent) in methanol (1.25 L), thionyl chloride (130 mL, 1.79mol, 2 equivalents) was added drop-wise at 0-5° C. Then the reactionmixture was stirred for 4 hours at 20-25° C. The reaction mixture wasconcentrated under reduced pressure. This crude material was stirred ina mixture of ethanol-methyl tert-butyl ether (1:4, 750 mL) for 30minutes and the solid was collected by filtration. The wet cake wasdried in a vacuum tray dryer for 8 hours at about 50° C. to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.03-2.23 (m, 2H), 3.06(d, 1H, J=12.0 Hz), 3.37 (dd, 2H, J=4.5 Hz, J=12.0 Hz), 3.75 (s, 3H),4.41-4.48 (m, 2H), 5.64 (bs, 1H), 9.43 (bs, 1H), 10.48 (bs, 1H).

Example 17B (2R,4S)-methyl1-(2-chloroacetyl)-4-hydroxypyrrolidine-2-carboxylate

To a suspension of Example 17A (100 g, 0.55 mol, 1 equivalent) inbenzene (2.5 L), chloroacetyl chloride (62.4 g, 0.50 mol, 1 equivalent)was added dropwise at 20-25° C. The reaction mixture was refluxed for 3hours. Then charcoal (2 g) was added, and the mixture was hot filteredthrough diatomaceous earth. The filtrate was concentrated under reducedpressure to get a solid. To this crude material, methyl tert-butyl ether(500 mL) was added and stirred for 30 minutes. The solid was collectedby filtration, and the wet cake was dried in a vacuum tray dryer for 5hours at about 50° C. to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.06-2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=11.1Hz), 3.76 (s, 3H), 3.76-3.86 (m, 2H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).

Example 17C(7S,8aR)-2-benzyl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione

To a solution of Example 17B (200 g, 0.90 mol, 1 equivalent) in2-ethoxyethanol (3.2 L), benzylamine (120 mL, 1.09 mol, 1.2 equivalents)was added. To this mixture, triethylamine (152 mL, 1.08 mol, 1.28equivalents) was added, and the mixture was refluxed for 20 hours. Thereaction mixture was cooled and concentrated under reduced pressure toafford crude product. This crude material was purified by columnchromatography on silica gel using a mixture of methanol-ethyl acetategradient (0-10%) to afford the title compound. ¹H NMR (300 MHz, CDCl₃) δppm 2.11 (m, 1H), 2.46 (m, 1H), 3.50 (m, 2H), 3.73 (d, 1H, J=16), 3.76(m, 1H), 4.00 (d, 1H, J=16), 4.45 (d, 1H, J=15), 4.50 (m, 2H), 4.72 (d,1H, J=15), 7.30 (m, 5H).

Example 17D (7S,8aR)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol

To a suspension of lithium aluminum hydride (50.7 g, 1.33 mol, 4equivalents) in tetrahydrofuran (1.3 L), Example 17C (87 g, 0.33 mol, 1equivalent) in tetrahydrofuran (1.3 L) was added slowly at about 15° C.Then the mixture was stirred at about 65° C. for 78 hours. The reactionmixture was cooled to 0-5° C. and quenched using ethyl acetate (430 mL),water (87 mL), 10% NaOH solution (175 mL), followed by water (260 mL)and stirred at 20-25° C. for 30 minutes. The suspension was filteredthrough diatomaceous earth, and the filtrate was concentrated. Thiscrude material was purified by column chromatography on silica gel usinga gradient of methanol-ethyl acetate (0-10%) to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.46-1.52 (m, 2H), 1.68 (t,1H, J=8.4 Hz), 1.918 (dd, 1H, J=5.7 Hz, J=7.2 Hz), 2.04-2.27 (m, 3H),2.67 (d, 1H, J=10.5 Hz), 2.79 (d, 2H, J=10.2 Hz), 3.23 (dd, 1H, J=6.9Hz, J=4.9 Hz), 3.47 (dd, 2H, J=4.2 Hz, J=17.7 Hz), 4.15-4.25 (m, 1H),4.73 (bs, 1H), 7.23-7.34 (m, 5H); ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 40.0,51.32, 52.62, 57.58, 60.72, 62.49, 63.12, 68.42, 127.29, 128.57, 129.23,138.83; MS (ESI) m/z 233 (M+H)⁺.

Example 17E(7S,8aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]-pyrazin-7-ol

To (7S,8aR)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 17D, 5g, 21.52 mmol) and solvent 2,2,2-trifluoroethanol (50 mL) were added to20% palladium hydroxide on carbon, wet (0.500 g) in a pressure bottle.The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen.The mixture was filtered through a nylon membrane to give a crude(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of the abovecrude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.0 g, 7 mmol) andtriethylamine (1.13 g, 11.2 mmol) in dichloromethane (40 mL) was slowlyadded a solution of 3-(trifluoromethyl)benzene-1-sulfonyl chloride(1.712 g, 7 mmol) in dichloromethane (2 mL). The solution was stirred atroom temperature for 4 hours. The solution was concentrated, dilutedwith ethyl acetate (100 mL), washed with water (20 mL), dried oversodium sulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel (dichloromethane/methanol=10:1) to give thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.43-1.58 (m, 2H), 1.97(m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H),3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H), 7.92 (m, 2H), 8.10 (m, 2H); MS(ESI) m/z 351 (M+H)⁺.

Example 18(7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of Example 17 (140 mg, 0.4 mmol) in tetrahydrofuran (5 mL)was added potassium tert-butoxide (0.7 mL, 1 M in tetrahydrofuran, 0.7mmol) followed by a solution of 2-bromo-5-cyclopropylpyrazine (88 mg,0.44 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at roomtemperature for 2 days. The mixture was concentrated, and the residuewas purified by chromatography on silica gel(dichloromethane/methanol=15:1) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.70-1.95 (m, 2H),2.08-2.40 (m, 6H), 2.98 (m, 1H), 3.57 (m, 1H), 3.69 (m, 1H), 3.82 (m,1H), 5.20 (m, 1H), 7.92 (m, 2H), 8.15 (m, 4H); MS (ESI) m/z 469 (M+H)⁺.

Example 19(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]-pyrazin-7-olExample 19A (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylatehydrochloride

To a suspension of trans-4-hydroxy-L-proline (100 g, 0.76 mol, 1equivalent) in methanol (850 mL), thionyl chloride (110 mL, 1.53 mol, 2equivalents) was added drop-wise at 0-5° C. Then the reaction mixturewas stirred for 4 hours at 20-25° C. The reaction mixture wasconcentrated under reduced pressure. The crude material was stirred in amixture of ethanol-methyl tert-butyl ether (1:4, 500 mL) for 30 minutesand the solid was collected by filtration. The wet cake was dried in avacuum tray dryer for 8 hours at about 50° C. to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.09-2.24 (m, 2H), 3.07 (d,1H, J=12.3 Hz), 3.35 (dd, 2H, J=4.2 Hz, J=11.7 Hz), 3.76 (s, 3H),4.42-4.51 (m, 2H), 5.59 (bs, 1H), 9.3 (bs, 1H), 10.3 (bs, 1H).

Example 19B (2S,4R)-methyl1-(2-chloroacetyl)-4-hydroxypyrrolidine-2-carboxylate

To a suspension of Example 19A (130 g, 0.72 mol, 1 equivalent) inbenzene (3.9 L), chloroacetyl chloride (81.1 g, 0.72 mol, 1 equivalent)was added dropwise at 20-25° C. The reaction mixture was refluxed for 5hours. Then, charcoal (500 mg) was added, and the reaction mixture washot filtered through diatomaceous earth. The filtrate was concentratedunder reduced pressure. To this crude material, methyl tert-butyl ether(650 mL) was added, and the mixture was stirred for 30 minutes. Thesolid was collected by filtration, and the wet cake was dried in avacuum tray dryer for 5 hours at about 50° C. to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.9-1.96 (m, 1H), 2.08-2.19(m, 1H), 3.36 (d, 1H, J=14.4 Hz), 3.65 (s, 3H), 3.66 (m, 2H), 4.33 (s,2H), 4.35 (m, 1H), 5.25 (bs, 1H); MS (ESI) m/z 222 (M+H)⁺.

Example 19C(7R,8aS)-2-benzyl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione

To a solution of Example 19B (75 g, 0.34 mol, 1 equivalent) in2-ethoxyethanol (1.2 L), benzylamine (44 mL, 0.41 mol, 1.2 equivalents)was added. Triethylamine (60 mL, 0.43 mol, 1.28 equivalents) was thenadded, and the resultant mixture was refluxed for 12 hours. The reactionmixture was cooled and concentrated under reduced pressure. This crudematerial was purified by column chromatography on silica gel using agradient of 0-10% methanol-ethyl acetate to provide the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.93-2.03 (m, 1H), 2.1-2.17 (m, 1H),3.23 (d, 1H, J=12.3 Hz), 3.55 (d, 1H, J=4.2 Hz), 3.63 (d, 1H, J=16.5Hz), 4.15 (m, 1H), 4.32 (bs, 1H), 4.47-4.59 (m, 3H), 5.16 (s, 1H),7.24-7.37 (m, 5H).

Example 19D (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol

To a suspension of Example 19C (60 g, 0.23 mol, 1 equivalent) intetrahydrofuran (900 mL), lithium aluminum hydride (2 M intetrahydrofuran, 460 mL, 0.92 mol, 4 equivalents) was added slowly atabout 15° C. Then, the mixture was stirred at about 65° C. for 78 hours.The reaction mixture was cooled to 0-5° C., quenched using ethyl acetate(300 mL), water (60 mL), 10% NaOH solution (60 mL), followed by water(60 mL), and the mixture was stirred at 20-25° C. for 30 minutes. Thesuspension was filtered through diatomaceous earth, and the filtrate wasconcentrated. This crude material was purified by column chromatographyon silica gel using a gradient of 0-10% methanol-ethyl acetate to affordthe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.46-1.49 (m, 2H),1.68, (t, 1H, J=9.9 Hz), 1.91 (dd, 1H, J=5.4 Hz, J=8.9 Hz), 2.04-2.13(m, 1H), 2.15-2.49 (m, 2H), 2.67 (d, 1H, J=10.3 Hz), 2.78 (d, 2H, J=5.4Hz), 3.25 (dd, 1H, J=4.5 Hz, J=8.9 Hz), 3.47 (dd, 2H, J=4.5 Hz, J=17.4Hz), 4.15-4.22 (m, 1H), 4.73 (bs, 1H), 7.23-7.318 (m, 5H); ¹³C NMR (75MHz, DMSO-d₆) δ ppm 39.74, 51.34, 52.64, 57.61, 60.72, 62.56, 63.16,68.46, 127.26, 128.54, 129.2, 138.84; MS (ESI) m/z 233 (M+H)⁺.

Example 19E(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]-pyrazin-7-ol

A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol(Example 19D, 1 g, 4.30 mmol) and ethanol (10 mL) was added to 20%palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. Themixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. Themixture was filtered through a nylon membrane to give a crudeintermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. The titlecompound was prepared according to the procedure described in Example17E substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.43-1.58 (m, 2H), 1.97 (m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H),3.20 (m, 1H), 3.62 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H),7.92 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 351 (M+H)⁺.

Example 20(7R,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 17, substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-olfor (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride followed by the procedurefor Example 18, substituting 2-chloro-6-(trifluoromethyl)pyridine for2-bromo-5-cyclopropylpyrazine. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.88 (m,2H), 2.22-2.32 (m, 3H), 2.60 (m, 1H), 2.92 (m, 1H), 3.00 (m, 1H), 3.67(m, 2H), 3.88 (m, 1H), 5.28 (m, 1H), 7.03 (d, 1H, J=7 Hz), 7.15 (m, 2H),7.48 (d, 1H, J=7 Hz), 7.74 (m 1H), 7.97 (m, 1H); MS (ESI) m/z 530(M+H)⁺.

Example 21(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of Example 19 (350 mg, 1 mmol) in tetrahydrofuran (10 mL)was added potassium tert-butoxide (1.6 mL, 1 M in tetrahydrofuran, 1.6mmol) followed by a solution of 2-bromo-5-cyclopropylpyrazine (239 mg,1.0 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at roomtemperature for 2 days. The mixture was concentrated, and the residuewas purified by chromatography on silica gel(dichloromethane/methanol=15:1) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.70-1.95 (m, 2H),2.08-2.40 (m, 6H), 2.98 (m, 1H), 3.57 (m, 1H), 3.69 (m, 1H), 3.82 (m,1H), 5.20 (m, 1H), 7.92 (m, 2H), 8.15 (m, 4H); MS (ESI) m/z 469 (M+H)⁺.

Example 22(7R,8aS)-7-(pyrazin-2-yloxy)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18, substituting Example 19 for Example 17 and substituting2-chloropyrazine for 2-bromo-5-cyclopropylpyrazine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.70-1.95 (m, 2H), 2.08-2.42 (m, 5H), 2.99 (m, 1H), 3.57(m, 1H), 3.69 (m, 1H), 3.83 (m, 1H), 5.23 (m, 1H), 7.93 (m, 2H), 8.15(m, 4H), 8.35 (s, 1H); MS (ESI) m/z 429 (M+H)⁺.

Example 23(7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18, substituting Example 19 for Example 17 and substituting2-bromo-6-cyclopropylpyrazine for 2-bromo-5-cyclopropylpyrazine. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.80 (m, 2H), 0.96 (m, 2H), 1.75 (m, 1H), 1.90(m, 1H), 2.08-2.40 (m, 6H), 2.99 (m, 1H), 3.51 (m, 1H), 3.68 (m, 1H),3.82 (m, 1H), 5.17 (m, 1H), 7.93 (m, 3H), 8.15 (m, 3H); MS (ESI) m/z 469(M+H)⁺.

Example 24(7R,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]-pyrazin-7-ol

The title compound was prepared according to the procedure described inExample 17, substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-olfor (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.46-1.58 (m, 2H), 1.97 (m, 2H), 2.12-2.36 (m, 3H), 2.90(m, 1H), 3.21 (m, 1H), 3.61 (m, 1H), 3.76 (m, 1H), 4.14 (m, 1H), 4.81(m, 1H), 7.96 (d, 2H, J=7 Hz), 8.04 (d, 2H, J=7 Hz); MS (ESI) m/z 351(M+H)⁺.

Example 25(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18, substituting Example 24 for Example 17. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.73-1.92 (m, 2H), 2.08-2.40(m, 6H), 2.98 (m, 1H), 3.57 (m, 1H), 3.65 (m, 1H), 3.80 (m, 1H), 5.20(m, 1H), 7.96 (d, 2H, J=7 Hz), 8.03 (s, 1H), 8.06 (d, 2H, J=7 Hz); 8.14(s, 1H); MS (ESI) m/z 469 (M+H)⁺.

Example 26(7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18 substituting Example 24 for Example 17 and substituting2-bromo-6-cyclopropylpyrazine for 2-bromo-5-cyclopropylpyrazine. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.89 (m, 2H), 0.98 (m, 2H), 1.75 (m, 1H), 1.90(m, 1H), 2.08-2.40 (m, 6H), 2.99 (m, 1H), 3.52 (m, 1H), 3.62 (m, 1H),3.80 (m, 1H), 5.17 (m, 1H), 8.00 (m, 5H), 8.18 (s, 1H); MS (ESI) m/z 469(M+H)⁺.

Example 27(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazineExample 27A(7R,8aS)-2-benzyl-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

To (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 19D,2.323 g, 10 mmol) in tetrahydrofuran (60 mL) at room temperature wasadded potassium tert-butoxide (14 mL, 1 M in tetrahydrofuran). After 10minutes, 2-bromo-5-cyclopropylpyrazine (2.249 g, 11.3 mmol) intetrahydrofuran (3 mL) was added. The mixture was stirred at roomtemperature for 2 days. The mixture was concentrated and diluted withdichloromethane (200 mL). This solution was washed with water (30 mL),dried over sodium sulfate, and filtered. The organic phase wasconcentrated. The residue was purified by chromatography on silica gel(dichloromethane/methanol=15:1) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.78 (m, 3H), 2.08-2.38(m, 5H), 2.70 (m, 1H), 2.83 (m, 2H), 3.53 (m, 3H), 5.24 (m, 1H), 7.28(m, 5H), 8.12 (m, 2H); MS (ESI) m/z 351 (M+H)⁺.

Example 27B(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

To a 100 mL pressure bottle was added Example 27A (2.78 g, 7.94 mmol) intetrahydrofuran (20 mL) and 20% palladium hydroxide on carbon (0.22 g,1.59 mmol). The mixture was stirred at 50° C. for 16 hours under 30 psiof hydrogen. The mixture was filtered through a nylon membrane to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (m, 2H), 0.93(m, 2H), 1.75 (m, 2H), 2.04-2.28 (m, 6H), 2.57 (m, 1H), 2.80 (m, 2H),2.95 (1H), 3.53 (m, 3H), 5.20 (m, 1H), 8.16 (m, 2H); MS (ESI) m/z 261(M+H)⁺.

Example 27C(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of Example 27B (50 mg, 0.192 mmol) and triethylamine (29.2mg, 0.288 mmol) in dichloromethane (1 mL) was added2-(trifluoromethyl)benzene-1-sulfonyl chloride (47 mg, 1.92 mmol). Themixture was stirred at room temperature for 16 hours. The mixture waspurified by chromatography on silica gel (ethyl acetate/hexane=4:1) togive the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (m, 2H),0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H), 2.22 (m, 2H), 2.33 (m, 1H),2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H), 3.64 (m, 2H), 3.82 (m, 1H),5.25 (m, 1H), 7.92 (m, 2H), 8.15 (m, 4H); MS (ESI) m/z 469 (M+H)⁺.

Example 28(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethoxy)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described in Example27C substituting 4-(trifluoromethoxy)benzene-1-sulfonyl chloride for2-(trifluoromethyl)-benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H),2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H),3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 7.65 (d, J=7 Hz, 2H), 7.90 (d,J=7 Hz, 2H), 8.15 (s, 2H); MS (ESI) m/z 485 (M+H)⁺.

Example 29(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(difluoromethoxy)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described in Example27C substituting 4-(difluoromethoxy)benzene-1-sulfonyl chloride for2-(trifluoromethyl)-benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H),2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H),3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 7.42 (d, J=7 Hz, 2H), 7.82 (d,J=7 Hz, 2H), 8.15 (s, 2H); MS (ESI) m/z 467 (M+H)⁺.

Example 30(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(difluoromethoxy)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described in Example27C substituting 3-(difluoromethoxy)benzene-1-sulfonyl chloride for2-(trifluoromethyl)-benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H),2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H),3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 7.20-7.70 (m, 4H), 8.15 (s,2H); MS (ESI) m/z 467 (M+H)⁺.

Example 31(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-fluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described in Example27C substituting 2-fluorobenzene-1-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.82 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H),2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H),3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 7.47 (m, 2H), 7.80 (m, 2H),8.15 (s, 2H); MS (ESI) m/z 419 (M+H)⁺.

Example 32(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-fluoro-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described in Example27C substituting 2-fluoro-5-(trifluoromethyl)benzene-1-sulfonyl chloridefor 2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.82 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H),2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H),3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 7.80 (m, 1H), 8.02 (m, 1H),8.15 (s, 2H), 8.22 (m, 1H); MS (ESI) m/z 487 (M+H)⁺.

Example 33(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-furylsulfonyl)octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described in Example27C substituting furan-2-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.82 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H),2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H),3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 6.76 (m, 1H), 7.22 (m, 1H),8.05 (m, 1H), 8.10 (s, 2H); MS (ESI) m/z 391 (M+H)⁺.

Example 34(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethoxy)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described in Example27C substituting 3-(trifluoromethoxy)benzene-1-sulfonyl chloride for2-(trifluoromethyl)-benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H),2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H),3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 7.70 (m, 1H), 7.81 (m, 3H),8.10 (s, 2H); MS (ESI) m/z 485 (M+H)⁺.

Example 35(8R*,8aS*)-8-[(5-chloropyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazineExample 35A 1-tert-butyl 3-methyl4-(3-methoxy-3-oxopropyl)piperazine-1,3-dicarboxylate

To a solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylatehydrochloride, (200 g, 0.82 mol) in methanol (1 L) was added methylacrylate (214 g, 2.46 mol) with stirring at approximately 25° C. underN₂ atmosphere, and the reaction mixture was refluxed at 70° C. for 48hours. The volatiles were removed under reduced pressure, and theresidue was partitioned between ethyl acetate (1.2 L) and water (2 L).The organic layer was separated and washed with water (1 L×2) and brine(500 mL), dried over Na₂SO₄, filtered and concentrated. The crudeobtained was purified by column chromatography over silica gel using30-40% ethyl acetate in petroleum ether to give the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 11.43 (s, 9H), 2.20-2.34 (m, 1H), 2.35-2.46(m, 1H), 2.48 (t, 2H, J=7.2 Hz), 2.76-2.90 (m, 1H), 2.90-3.12 (m, 2H),3.12-3.30 (m, 1H), 3.32 (t, 1H, J=4.5 Hz), 3.35-3.44 (m, 1H), 3.67 (s,3H), 3.71 (s, 3H) 3.83-3.94 (m, 1H).

Example 35B 2-tert-butyl 7-methyl8-oxohexahydropyrrolo[1,2-a]pyrazine-2,7(111)-dicarboxylate

To a solution of 1-tert-butyl 3-methyl4-(3-methoxy-3-oxopropyl)piperazine-1,3-dicarboxylate (Example 35A, 180g, 0.545 mol) in tetrahydrofuran (1.3 L) was added potassium t-butoxide(98 g, 0.872 mol) with stirring at 0-5° C. under N₂ atmosphereportion-wise over a period of 30 minutes. The reaction mixture wasstirred at ambient temperature for 2 hours. The reaction was thenquenched with saturated aqueous ammonium chloride solution (500 mL) andextracted with ethyl acetate (1 L). The organic layer was separated,washed with brine (500 mL), dried over Na₂SO₄, filtered and concentratedto afford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.48 (s,9H), 2.28-2.35 (m, 2H), 2.65-2.83 (m, 1H), 2.83-3.12 (m, 3H), 3.43 (t,1H, J=8.4 Hz), 3.61 (t, 1H, J=8.4 Hz), 3.78 (s, 3H), 3.98-4.20 (bs, 1H),4.20-4.45 (bs, 1H).

Example 35C tert-butyl8-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

A mixture of 2-tert-butyl 7-methyl8-oxohexahydropyrrolo[1,2-a]pyrazine-2,7(1H)-dicarboxylate (Example 35B,131 g, 0.44 mol), dimethyl sulfoxide (530 mL), NaCl (25.6 g, 0.44 mol)and water (32 g, 1.75 mol) was heated to 130° C. and maintained at thattemperature for 2 hours. The reaction mixture was cooled, diluted withwater (1 L) and extracted with ethyl acetate (1 L×2). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was chromatographed over silica gel eluting with 30-40% ethylacetate in petroleum ether to afford the title compound. ¹H NMR (300MHz, CDCl₃) δ ppm 1.48 (s, 9H), 2.23-2.42 (m, 3H), 2.47-2.60 (m, 1H),2.60-2.78 (m, 1H), 2.82-2.98 (m, 1H), 3.02-3.10 (m, 1H), 3.32-3.40 (m,1H), 3.65-3.85 (m, 1H), 3.99-4.20 (bs, 1H), 4.20-4.45 (bs, 1H).

Example 35D (8R*,8aS*)-tert-Butyl8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of Example 35C (46 g, 0.192 mol) in methanol (460 mL) wasadded NaBH₄ (13 g, 0.345 mol) at approximately 0° C., and the mixturewas stirred at ambient temperature for 1 hour. The reaction mixture wasquenched with saturated ammonium chloride solution (100 mL), and thevolatiles were removed under reduced pressure. The residue obtained waspartitioned between ethyl acetate (500 mL) and water (250 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated. The material obtained was purified by columnchromatography over silica gel using 5-6% methanol in chloroform to getthe first eluting product (Example 36A, 5.3 g) and second elutingproduct (Example 35D, 5.1 g) together with 20 g of a mixture of bothdiastereomers.

By repeating the chromatography procedure, more of Example 36A wascollected. The mixture of diastereomers (enriched with Example 35D) wasderivatized to benzoyl derivative and separated as described below.

Example 35E (8R*,8aS*)-tert-butyl8-(benzoyloxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of a mixture of diastereomers Example 35D and Example 36A(33 g, 0.136 mol) in dichloromethane and pyridine (1:1, 300 mL) wasadded 4-(dimethylamino)pyridine (4 g, 0.034 mol) and then benzoylchloride (30 g, 0.163 mol) at 0° C. under a N₂ atmosphere. The reactionmixture was stirred at ambient temperature for 2 hours and thenconcentrated to remove the volatiles. The residue was taken into ethylacetate (500 mL) and then washed with water (250 mL×2), 5% citric acidin water (250 mL×2), and brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified over silica gel using 20% ethyl acetate in petroleum ether toget the first eluting compound (Example 35E, found to be Example 35Dafter saponification, 13.5 g) and a mixture of Example 35E and itsdiastereomer (15 g). 1H NMR (300 MHz, CDCl₃) δ ppm 1.48 (s, 9H),1.72-1.88 (m, 1H), 2.18-2.32 (m, 2H), 2.40-2.60 (m, 2H), 2.63-2.85 (m,1H), 2.85-3.06 (m, 2H), 3.06-3.18 (m, 1H), 4.06 (bs, 1H), 3.38 (bs, 1H),5.02-5.12 (m, 1H), 7.46 (t, 2H, J=7.5 Hz), 7.9 (t, 1H, J=7.5 Hz), 8.06(d, 2H, J=7.5 Hz).

Mixtures of the diastereomeric esters were subjected to furtherchromatographic passes to obtain additional quantities of eachdiastereomer.

Example 35D From Saponification of Example 35E (8R*,8aS*)-tert-Butyl8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of Example 35E (8 g, 0.023 mol) in methanol (25 mL) wasadded potassium t-butoxide (14.5 g, 0.129 mol), and the reaction mixturewas stirred at room temperature for 30 minutes. The reaction mixture wasconcentrated, the residue was diluted with 5% citric acid in water (100mL), and the mixture was extracted with ethyl acetate (50 mL×2). Thecombined organic layers were discarded. The aqueous layer was basifiedusing K₂CO₃ to pH 8-9 and extracted with ethyl acetate (50 mL×2). Thecombined organic layers were dried over Na₂SO₄ and concentrated to givethe title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.48 (s, 9H),1.56-1.69 (m, 1H), 1.86-1.97 (m, 1H), 2.10-2.35 (m, 3H), 2.35-2.48 (m,1H), 2.52-2.72 (m, 1H), 2.78-2.97 (m, 2H), 3.03 (dt, 1H, J=17.1, 2.4Hz), 3.92-4.15 (m, 2H), 4.32 (bs, 1H).

The same procedure was applied to the diastereomer to provide additionalExample 36A.

Example 35F(8R*,8aS*)-8-(5-chloropyridin-2-yloxy)octahydropyrrolo[1,2-a]pyrazine

(8R*,8aS*)-tert-Butyl8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Example 35D,0.969 g, 4.0 mmol) and 2,5-dichloropyridine (0.651 g, 4.40 mmol) weretreated with potassium tert-butoxide (0.987 g, 8.80 mmol) in drytetrahydrofuran (5 mL). The mixture was heated to 80° C. and stirred for16 hours. After the mixture cooled to room temperature, the mixture waspurified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=222 nm) togive the tert-butoxycarbonyl protected product, tert-butyl8-(5-chloropyridin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.This tert-butoxycarbonyl compound was dissolved in dichloromethane (5mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture wasstirred at room temperature for 3 hours. The mixture was concentratedand then purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, elutedwith pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol,UV=220 nm) to give the title compound. ¹H NMR (300 MHz, methanol-d₄) δppm 1.72-1.86 (m, 1H), 2.08-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.69-2.80(m, 2H), 2.87-2.98 (m, 1H), 2.99-3.21 (m, 3H), 5.51 (ddd, 1H, J=7, 4, 2Hz), 6.77 (d, 1H, J=9 Hz), 7.65 (dd, 1H, J=8, 2 Hz), 8.07 (d, 1H, J=2Hz); MS (DCI) m/z 254 (M+H)⁺.

Example 35G(8R*,8aS*)-8-[(5-chloropyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine

To a mixture of Example 35F (120 mg, 0.473 mmol) in dry CH₂Cl₂ was added3-(trifluoromethyl)benzene-1-sulfonyl chloride (139 mg, 0.568 mmol)followed by triethylamine (0.3 mL). The resultant mixture was stirred atroom temperature for 16 hours and then purified by preparative HPLC(Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammoniumbicarbonate-ammonium hydroxide/methanol, UV=222 nm) to give the titlecompound. ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.65-1.78 (m, 1H),2.29-2.55 (m, 6H), 2.98-3.09 (m, 2H), 3.72-3.82 (m, 1H), 4.04 (ddd, 1H,J=17, 9, 1 Hz), 4.94-5.04 (m, 1H), 6.81 (d, 1H, J=8 Hz), 7.68 (dd, 1H,J=8, 2 Hz), 7.84 (t, 1H, J=8 Hz), 7.98-8.10 (m, 4H); MS (DCI) m/z 462(M+H)⁺.

Example 36(8R*,8aR*)-8-[(5-chloropyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine(8R*,8aR*)-tert-Butyl8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

The title compound was prepared as described in Examples 35A through35D. Example 36A was obtained as the faster eluting diastereomer inExample 35D. Additional quantities of Example 36A were obtained usingthe procedures described in Example 35E followed by the saponificationprocedure described for Example 35D. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.48(s, 9H), 1.68-1.85 (m, 2H), 1.85-2.00 (bs, 1H), 2.00-2.17 (m, 2H),2.18-2.30 (m, 1H), 2.78-2.98 (m, 2H), 3.03 (d, 1H, J=11.1 Hz), 3.20 (dt,1H, J=17.7, 2.4 Hz), 4.07 (bs, 1H), 4.15-4.32 (m, 2H).

(8R*,8aR*)-8-(5-chloropyridin-2-yloxy)octahydropyrrolo[1,2-a]pyrazine

(8R*,8aR*)-tert-Butyl8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Example 36A,0.969 g, 4.0 mmol) and 2,5-dichloropyridine (0.651 g, 4.40 mmol) weretreated with potassium tert-butoxide (0.987 g, 8.80 mmol) in drytetrahydrofuran (5 mL). The mixture was heated to 80° C. and stirred for16 hours. After the mixture cooled to room temperature, the mixture waspurified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=222 nm) togive the tert-butoxycarbonyl protected product, (8R*,8aR*)-tert-butyl8-(5-chloropyridin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.This tert-butoxycarbonyl compound was dissolved in dichloromethane (5mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture wasstirred at room temperature for 3 hours. The mixture was concentratedand then purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, elutedwith pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol,UV=220 nm) to give the title compound. ¹H NMR (300 MHz, methanol-d₄) δppm 1.72-1.86 (m, 1H), 2.08-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.69-2.80(m, 2H), 2.87-2.98 (m, 1H), 2.99-3.21 (m, 3H), 5.51 (ddd, 1H, J=7, 4, 2Hz), 6.77 (d, 1H, J=9 Hz), 7.65 (dd, 1H, J=8, 2 Hz), 8.07 (d, 1H, J=2Hz); MS (DCI) m/z 254 (M+H)⁺.

Example 36C(8R*,8aR*)-8-[(5-chloropyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 35G substituting Example 36B for Example 35F. ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.74-1.88 (m, 1H), 2.12-2.49 (m, 6H), 3.09-3.18 (m,2H), 3.76 (dd, 1H, J=11, 2 Hz), 3.89 (d, 1H, J=8 Hz), 5.54 (ddd, 1H,J=7, 4, 2 Hz), 6.65 (d, 1H, J=8 Hz), 7.65 (dd, 1H, J=8, 2 Hz), 7.82 (t,1H, J=7 Hz), 7.90 (s, 1H), 7.95-8.02 (m, 2H), 8.12 (d, 1H, J=2 Hz); MS(DCI) m/z 462 (M+H)⁺.

Example 37(7S,8aS)—N-(diphenylmethyl)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamideExample 37A (7S,8aS)-tert-butyl7-(benzhydrylcarbamoyl)hexahydropyrrolo[1,2-a]-pyrazine-2(1H)-carboxylate

To a solution of(7S,8aS)-2-(tert-butoxycarbonyl)octahydropyrrolo[1,2-a]pyrazine-7-carboxylicacid (80 mg, 0.296 mmol) in dichloromethane (2 mL) was added a solutionof 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (68.9 mg, 0.444 mmol)and hydroxybenzotriazole hydrate (40.0 mg, 0.296 mmol) indichloromethane (1 mL). The mixture was stirred at room temperature for1 hour, and then diphenylmethanamine (54.2 mg, 0.296 mmol) was added.After stirring for three days the mixture was poured into water (10 mL).The mixture was extracted with dichloromethane (3×5 mL). The organicfractions were concentrated, and the residue was purified by flashchromatography (dichloromethane/methanol=25:1) to give the titlecompound. MS (ESI) m/z 436 (M+H)⁺.

Example 37B(7S,8aS)—N-benzhydryloctahydropyrrolo[1,2-a]pyrazine-7-carboxamide

To Example 37A (109 mg, 0.25 mmol) in dichloromethane (0.5 mL) was addedhydrochloric acid (0.5 mL, 4 N in dioxane). The mixture was stirred atroom temperature overnight and concentrated to give the title compoundas a hydrochloric acid salt. MS (ESI) m/z 336 (M+H)⁺.

Example 37C(7S,8aS)—N-(diphenylmethyl)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide

To a solution of Example 37B (50 mg, 0.134 mmol) in dichloromethane (1mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (32.9 mg,0.134 mmol) followed by triethylamine (0.2 mL). The mixture was stirredat room temperature overnight and then concentrated. The residue waspurified by flash chromatography (dichloromethane/methanol=50:1) to givethe title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.58 (m, 1H), 2.03(m, 1H), 2.27-2.41 (m, 5H), 2.86 (m, 1H), 3.06 (m, 1H), 3.22 (m, 1H),3.78 (m, 1H), 3.90 (m, 1H), 6.10 (m, 1H), 7.08 (m, 2H), 7.15 (m, 4H),7.26 (m, 4H), 7.70 (m, 1H), 7.90 (m, 3H), 8.00 (s, 1H); MS (ESI) m/z 544(M+H)⁺.

Example 38(7S,8aS)—N-(diphenylmethyl)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide

The title compound was prepared according to the procedure described inExample 37C substituting 4-(trifluoromethyl)benzene-1-sulfonyl chloridefor 3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.25 (m, 1H), 2.03 (m, 1H), 2.27-2.41 (m, 5H), 2.86 (m,1H), 3.06 (m, 1H), 3.22 (m, 1H), 3.78 (m, 1H), 3.90 (m, 1H), 6.10 (m,1H), 7.10 (m, 5H), 7.26 (m, 5H), 7.84 (m, 2H), 7.87 (m, 2H); MS (ESI)m/z 544 (M+H)⁺.

Example 39(7S,8aS)—N-(diphenylmethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine-7-carboxamide

The title compound was prepared according to the procedure described inExample 37C substituting 4-fluoro-3-(trifluoromethyl)benzene-1-sulfonylchloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.25 (m, 1H), 2.03 (m, 1H), 2.27-2.41 (m, 5H), 2.86(m, 1H), 3.06 (m, 1H), 3.22 (m, 1H), 3.78 (m, 1H), 3.90 (m, 1H), 6.10(m, 1H), 7.10 (m, 5H), 7.26 (m, 5H), 7.97 (m, 3H); MS (ESI) m/z 562(M+H)⁺.

Example 40(7S,8aS)—N-(4,4,4-trifluorobutyl)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine-7-carboxamide

The title compound was prepared according to the procedure described inExample 37 substituting 4,4,4-trifluorobutan-1-amine fordiphenylmethanamine ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.50-2.50 (m, 11H),3.18 (m, 5H), 3.85 (m, 2H), 7.71 (m, 1H), 7.88 (m, 1H), 7.96 (m, 1H),8.03 (s, 1H); MS (ESI) m/z 488 (M+H)⁺.

Example 41(7S,8aS)-7-[4-(trifluoromethoxy)phenoxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of Example 19 (92 mg, 0.26 mmol),4-(trifluoromethoxy)phenol (47 mg, 0.26 mmol), and triphenylphosphine(104 mg, 0.396 mmol) in anhydrous tetrahydrofuran (1.2 mL) at ambienttemperature was added diisopropyl azodicarboxylate (0.080 mL, 0.39 mmol)dropwise. The reaction was allowed to stir for 16 hours and then themixture was concentrated. The residue was purified via flashchromatography (0% to 70% ethyl acetate/hexanes). This material wastriturated with diethyl ether and the solvent was decanted. Theresulting solid was dried to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.40-1.27 (m, 1H), 2.23-2.02 (m, 3H), 2.47-2.35 (m, 3H),3.08-2.95 (m, 2H), 3.67 (d, 1H, J=11 Hz), 3.82 (d, 1H, J=10 Hz),4.90-4.79 (m, 1H), 6.90 (d, 2H, J=9 Hz), 7.24 (d, 2H, J=8 Hz), 7.91 (t,1H, J=8 Hz), 7.98 (s, 1H), 8.08 (d, 1H, J=8.0), 8.14 (d, 1H, J=8 Hz); MS(ESI+) m/z 511 (M+H)⁺.

Example 42(7S,8aS)-7-(4-tert-butylphenoxy)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 41 substituting 4-tert-butylphenol for4-(trifluoromethoxy)phenol. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.22 (s,9H), 1.38-1.26 (m, 1H), 2.22-2.01 (m, 3H), 2.48-2.33 (m, 3H), 3.06-2.93(m, 2H), 3.66 (d, 1H, J=11 Hz), 3.81 (d, 1H, J=10 Hz), 4.83-4.72 (m,1H), 6.72 (d, 2H, J=9 Hz), 7.24 (d, 2H, J=9 Hz), 7.91 (t, 1H, J=8 Hz),7.97 (s, 1H), 8.08 (d, 1H, J=8 Hz), 8.14 (d, 1H, J=8 Hz); MS (ESI+) m/z483 (M+H)⁺.

Example 43(7S,8aS)-7-[4-(1H-imidazol-1-yl)phenoxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 41 substituting 4-(1H-imidazol-1-yl)phenol for4-(trifluoromethoxy)phenol. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.42-1.29(m, 1H), 2.24-2.02 (m, 3H), 2.48-2.36 (m, 3H), 3.09-2.94 (m, 2H),3.73-3.62 (m, 1H), 3.89-3.78 (m, 1H), 4.94-4.83 (m, 1H), 6.98-6.89 (m,2H), 7.08-7.03 (m, 1H), 7.54-7.45 (m, 2H), 7.65-7.57 (m, 1H), 7.96-7.87(m, 1H), 7.98 (s, 1H), 8.18-8.04 (m, 3H); MS (ESI+) m/z 493 (M+H).

Example 44(7R,8aS)-7-[(6-cyclopropylpyridazin-3-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of Example 19 (220 mg, 0.628 mmol) in tetrahydrofuran (5mL) was added potassium tert-butoxide (1 mL, 1 M in tetrahydrofuran, 1mmol) followed by a solution of 3-chloro-6-cyclopropylpyridazine (121mg, 0.785 mmol) in tetrahydrofuran (1 mL). The mixture was stirred atroom temperature for 18 hours. The mixture was concentrated, and theresidue was purified by chromatography on silica gel (ethyl acetate) togive the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90-1.02 (m,4H), 1.78-1.92 (m, 2H), 2.08-2.42 (m, 6H), 2.99 (m, 1H), 3.60 (m, 1H),3.65 (m, 1H), 3.82 (m, 1H), 5.35 (m, 1H), 7.05 (d, 1H, J=5 Hz), 7.42 (d,1H, J=5 Hz), 7.92 (m, 2H), 8.12 (m, 2H); MS (ESI) m/z 469 (M+H)⁺.

Example 45(7R,8aS)-7-[(6-cyclopropylpyridazin-3-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 17E substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-olfor (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride followed by the proceduredescribed in Example 18 substituting 3-chloro-6-cyclopropylpyridazinefor 2-bromo-5-cyclopropylpyrazine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.93-1.03 (m, 4H), 1.80 (m, 1H), 1.92 (m, 1H), 2.08-2.43 (m, 6H), 2.99(m, 1H), 3.61 (m, 2H), 3.81 (m, 1H), 5.18 (m, 1H), 7.05 (d, 1H, J=5 Hz),7.42 (d, 1H, J=5 Hz), 7.96 (d, 2H, J=7 Hz), 8.04 (d, 2H, J=7 Hz); MS(ESI) m/z 469 (M+H)⁺.

Example 46(7R,8aS)-7-[(4-cyclopropylpyrimidin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 17E substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-olfor (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol followed by theprocedure described in Example 18 substituting2-chloro-4-cyclopropylpyrimidine for 2-bromo-5-cyclopropylpyrazine. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.00 (m, 4H), 1.76 (m, 1H), 1.88 (m, 1H),2.08-2.42 (m, 6H), 2.99 (m, 1H), 3.51 (m, 1H), 3.68 (m, 1H), 3.82 (m,1H), 5.16 (m, 1H), 7.05 (d, 1H, J=5 Hz), 7.93 (m, 2H), 8.11 (m, 2H),8.32 (d, 1H, J=5 Hz); MS (ESI) m/z 469 (M+H)⁺.

Example 47(7R,8aS)-7-[(4-cyclopropylpyrimidin-2-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 17E substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-olfor (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride followed by the proceduredescribed in Example 18 substituting 2-chloro-4-cyclopropylpyrimidinefor 2-bromo-5-cyclopropylpyrazine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02(m, 4H), 1.75 (m, 1H), 1.90 (m, 1H), 2.05-2.43 (m, 6H), 2.98 (m, 1H),3.51 (m, 1H), 3.62 (m, 1H), 3.81 (m, 1H), 5.17 (m, 1H), 7.05 (d, 1H, J=5Hz), 7.96 (d, 2H, J=7 Hz), 8.04 (d, 2H, J=7 Hz), 8.32 (d, 1H, J=5 Hz);MS (ESI) m/z 469 (M+H)⁺.

Example 481-(4-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}phenyl)ethanone

The title compound was prepared according to the procedure described inExample 27C substituting 4-acetylbenzene-1-sulfonyl chloride for2-(trifluoromethyl)-benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.72 (m, 1H), 1.90 (m, 1H),2.05-2.40 (m, 6H), 2.64 (s, 3H), 2.98 (m, 1H), 3.55 (m, 1H), 3.62 (m,1H), 3.80 (m, 1H), 5.20 (m, 1H), 7.88 (d, 2H, J=7 Hz), 8.11 (s, 2H),8.38 (d, 2H, J=7 Hz); MS (ESI) m/z 443 (M+H)⁺.

Example 49(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazineExample 49A (7S,8aS)-tert-butyl7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of (7S,8aS)-tert-butyl7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Wuxi Pharma,0.485 g, 2 mmol) in tetrahydrofuran (0.3 mL) was added potassiumtert-butoxide (2.8 mL, 1 M in tetrahydrofuran, 2.8 mmol) followed by asolution of 2-bromo-5-cyclopropylpyrazine (446 mg, 2.24 mmol) intetrahydrofuran (1 mL). The mixture was stirred at room temperature for16 hours. The mixture was concentrated, and the residue was purified bychromatography on silica gel (ethyl acetate) to give the titledcompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H),1.39 (s, 9H), 1.90 (m, 2H), 2.09 (m, 1H), 2.40 (m, 3H), 2.90 (m, 2H),3.08 (m, 1H), 3.28 (m, 1H), 3.86-4.08 (m, 2H), 5.27 (m, 1H), 8.11 (m,2H); MS (ESI) m/z 361 (M+H)⁺.

Example 49B(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

To Example 49A (640 mg, 1.776 mmol) in dichloromethane (2 mL) was addedhydrochloric acid (3 mL, 4 N in dioxane). The mixture was stirred atroom temperature overnight and concentrated to give the compound as ahydrochloric acid salt. MS (ESI) m/z 261 (M+H)⁺.

Example 49C(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of Example 49B (200 mg, 0.674 mmol)) in dichloromethane (3mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (198 mg,0.809 mmol) followed by triethylamine (0.3 mL). The mixture was stirredat room temperature overnight and then concentrated. The residue waspurified by flash chromatography (ethyl acetate/hexane=1:1) to give thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m,2H), 1.38 (m, 1H), 2.04-2.20 (m, 4H), 2.42 (m, 3H), 3.00 (m, 2H), 3.66(m, 1H), 3.82 (m, 1H), 5.20 (m, 1H), 7.92 (m, 1H), 7.98 (m, 1H), 8.03(m, 1H), 8.11 (m, 3H); MS (ESI) m/z 469 (M+H)⁺.

Example 50(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 49C substituting 4-(trifluoromethyl)benzene-1-sulfonyl chloridefor 3-(trifluoromethyl)benzene-1-sulfonyl chloride ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.38 (m, 1H), 2.04-2.20 (m,4H), 2.42 (m, 3H), 3.00 (m, 1H), 3.57 (m, 1H), 3.66 (m, 1H), 3.82 (m,1H), 5.20 (m, 1H), 7.80 (m, 2H), 8.02 (m, 3H), 8.11 (s, 1H); MS (ESI)m/z 469 (M+H)⁺.

Example 51(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-fluoro-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 27C substituting 3-fluoro-5-(trifluoromethyl)benzene-1-sulfonylchloride for 2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.78-1.88 (m, 2H),2.08-2.48 (m, 6H), 3.00 (m, 1H), 3.56 (m, 1H), 3.68 (m, 1H), 3.84 (m,1H), 5.20 (m, 1H), 7.85 (m, 1H), 8.00 (m, 1H), 8.12 (s, 2H), 8.17 (m,1H); MS (ESI) m/z 487 (M+H)⁺.

Example 52(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 27C substituting 4-fluoro-3-(trifluoromethyl)benzene-1-sulfonylchloride for 2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.80 (m, 2H), 0.90 (m, 2H), 1.78-1.88 (m, 2H),2.06-2.48 (m, 6H), 3.00 (m, 1H), 3.56 (m, 1H), 3.68 (m, 1H), 3.84 (m,1H), 5.20 (m, 1H), 7.85 (m, 1H), 8.00 (m, 1H), 8.11 (s, 2H), 8.17 (m,1H); MS (ESI) m/z 487 (M+H)⁺.

Example 53(7R,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 27C substituting 3-tert-butylbenzene-1-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.90 (m, 2H), 1.32 (s, 9H), 1.75 (m, 1H),1.88 (m, 1H), 1.98-2.30 (m, 6H), 3.00 (m, 1H), 3.56 (m, 1H), 3.68 (m,1H), 3.84 (m, 1H), 5.20 (m, 1H), 7.58 (m, 2H), 7.67 (s, 1H), 7.78 (m,1H), 8.11 (s, 2H); MS (ESI) m/z 457 (M+H)⁺.

Example 54(7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 17 substituting 4-(trifluoromethyl)benzene-1-sulfonyl chloridefor 3-(trifluoromethyl)benzene-1-sulfonyl chloride followed by theprocedure described in Example 18. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80(m, 2H), 0.92 (m, 2H), 1.38 (m, 1H), 2.04-2.20 (m, 4H), 2.42 (m, 3H),3.57 (m, 1H), 3.00 (m, 1H), 3.66 (m, 1H), 3.82 (m, 1H), 5.20 (m, 1H),7.98 (d, 2H, J=7 Hz), 8.03 (d, 2H, J=7 Hz), 8.15 (s, 2H); MS (ESI) m/z469 (M+H)⁺.

Example 55(7R,8aS)-2-[(3-chlorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 27C substituting 3-chlorobenzene-1-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.90 (m, 2H), 1.75 (m, 1H), 1.88 (m, 1H),1.98-2.30 (m, 6H), 3.00 (m, 1H), 3.56 (m, 1H), 3.68 (m, 1H), 3.84 (m,1H), 5.20 (m, 1H), 7.65 (m, 2H), 7.67 (s, 1H), 7.82 (m, 1H), 8.11 (s,2H); MS (ESI) m/z 435 (M+H)⁺.

Example 56(7R,8aS)-2-[(4-tert-butylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 27C substituting 4-tert-butylbenzene-1-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.80 (m, 2H), 0.90 (m, 2H), 1.32 (s, 9H), 1.75 (m, 1H),1.88 (m, 1H), 1.98-2.35 (m, 6H), 2.97 (m, 1H), 3.56 (m, 2H), 3.77 (m,1H), 5.20 (m, 1H), 7.62 (s, 4H), 8.12 (s, 2H); MS (ESI) m/z 457 (M+H)⁺.

Example 57(7R,8aS)-2-[(3-tert-butyl-4-methoxyphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

To a solution of the product from Example 27B (30 mg, 0.115 mmol) indichloromethane (1 mL) was added3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride (36 mg, 0.138 mmol)and diisopropylethylamine (0.040 mL, 0.23 mmol). The resulting mixturewas stirred at room temperature for 90 minutes. Water (2 mL) was added,and the mixture was extracted with dichloromethane (2×2 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a crude product. Purification by columnchromatography on silica gel eluting with a solvent gradient of 0-60%ethyl acetate in hexanes gave the titled compound. ¹H NMR (300 MHz,CDCl₃) δ ppm 0.87-1.00 (m, 4H), 1.38 (s, 9H), 1.73-1.87 (m, 1H),1.91-2.03 (m, 2H), 2.08 (t, J=10.51 Hz, 1H), 2.31 (dd, J=10.17, 5.09 Hz,1H), 2.37-2.48 (m, 2H), 2.48-2.60 (m, 1H), 2.91-3.05 (m, 1H), 3.63 (dd,J=10.17, 6.78 Hz, 1H), 3.68-3.76 (m, 1H), 3.83-3.90 (m, 1H), 3.90 (s,3H), 5.23-5.35 (m, 1H), 6.94 (d, J=9.16 Hz, 1H), 7.57-7.66 (m, 2H), 7.91(d, J=1.36 Hz, 1H), 8.02 (d, J=1.70 Hz, 1H); MS (ESI) m/z 487.1 (M+H)⁺.

Example 58(7R,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazineExample 58A 2-(benzylthio)-6-tert-butylpyridine

To a solution of benzyl mercaptan (0.22 mL, 1.87 mmol) in anhydrousN,N-dimethylformamide (10 mL) was added a 1.0 M solution of potassiumtert-butoxide in tetrahydrofuran (1.87 mL, 1.87 mmol) dropwise over 2minutes. To the resulting suspension was added2-bromo-6-tert-butylpyridine (0.20 g, 0.93 mmol), and the resultingmixture was stirred at 50° C. for 16 hours. The cooled mixture waspoured into water (50 mL) and extracted with ethyl acetate (50 mL), andthe ethyl acetate layer was dried over Na₂SO₄, filtered and concentratedin vacuo to give a crude product. Purification by column chromatographyon silica gel using hexanes gave the titled compound. ¹H NMR (300 MHz,CDCl₃) δ ppm 1.35 (s, 9H), 4.50 (s, 2H), 6.93-7.03 (m, 2H), 7.17-7.45(m, 6H); MS (APCI) m/z 258.3 (M+H)⁺.

Example 58B 6-tert-butylpyridine-2-sulfonyl chloride

To a solution of the product from Example 58A (0.10 g, 0.389 mmol) inacetic acid (1 mL) was added water (0.5 mL) and N-chlorosuccinimide(0.21 g, 1.55 mmol), and the resulting mixture was stirred at roomtemperature for 90 minutes. Volatiles were removed by evaporation withdry N₂ and the residue was partitioned between water and ethyl acetate(2×). The combined ethyl acetate extracts were dried over Na₂SO₄,filtered and concentrated in vacuo to give a semisolid that wastriturated with hexanes. The hexane layer was removed, and the resultingsolids were rinsed with hexanes (2×). The combined hexane layers werecombined and concentrated in vacuo to give the title compound. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 7.68 (d, J=7.54 Hz, 1H), 7.82-8.01(m, 2H); MS (APCI) m/z 234.3 (M+H)⁺.

Example 58C(7R,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described in Example57, substituting the product from Example 58B for3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride. ¹H NMR (300 MHz,CDCl₃) δ ppm 0.89-0.98 (m, 4H), 1.39 (s, 9H), 1.74-1.90 (m, 1H),1.90-2.03 (m, 2H), 2.27-2.60 (m, 3H), 2.60-2.73 (m, 1H), 2.90-3.06 (m,2H), 3.67 (dd, J=9.92, 6.74 Hz, 1H), 3.90 (d, J=13.49 Hz, 1H), 4.06 (d,J=10.71 Hz, 1H), 5.31 (q, J=5.82 Hz, 1H), 7.50 (dd, J=7.54, 1.19 Hz,1H), 7.71-7.84 (m, 2H), 7.92 (d, J=1.59 Hz, 1H), 8.03 (d, J=1.19 Hz,1H); MS (ESI) m/z 458.0 (M+H)⁺.

Example 59(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(morpholin-4-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 58, substituting 4-(6-bromopyridin-2-yl)morpholine for2-bromo-6-tert-butylpyridine. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.86-1.01(m, 4H), 1.72-1.89 (m, 1H), 1.91-2.03 (m, 2H), 2.28-2.61 (m, 4H),2.84-3.04 (m, 2H), 3.50-3.59 (m, 4H), 3.67 (dd, J=9.92, 6.74 Hz, 1H),3.77-3.92 (m, 5H), 3.93-4.06 (m, J=7.14 Hz, 1H), 5.25-5.37 (m, 1H), 6.76(d, J=8.73 Hz, 1H), 7.17-7.25 (m, 1H), 7.63 (dd, J=8.53, 7.34 Hz, 1H),7.92 (d, J=1.59 Hz, 1H), 8.03 (d, J=1.19 Hz, 1H); MS (ESI) m/z 487.1(M+H)⁺.

Example 60(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(piperidin-1-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 58, substituting 2-bromo-6-(piperidin-1-yl)pyridine for2-bromo-6-tert-butylpyridine. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.89-0.99(m, 4H), 1.59-1.70 (m, 6H), 1.74-1.90 (m, 1H), 1.90-2.03 (m, 2H),2.27-2.65 (m, 4H), 2.83-3.07 (m, 2H), 3.50-3.61 (m, 4H), 3.66 (dd,J=9.83, 6.78 Hz, 1H), 3.78-3.91 (m, 1H), 3.96-4.07 (m, 1H), 5.22-5.41(m, 1H), 6.74 (d, J=8.48 Hz, 1H), 7.13 (d, J=6.78 Hz, 1H), 7.54 (dd,J=8.65, 7.29 Hz, 1H), 7.92 (d, J=1.36 Hz, 1H), 8.03 (d, J=1.36 Hz, 1H);MS (ESI) m/z 485.1 (M+H)⁺.

Example 61(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(pyrrolidin-1-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 58, substituting 2-bromo-6-(pyrrolidin-1-yl)pyridine for2-bromo-6-tert-butylpyridine. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.89-0.99(m, 4H), 1.75-1.91 (m, 1H), 1.90-2.08 (m, 6H), 2.34 (dd, J=9.91, 5.16Hz, 1H), 2.38-2.61 (m, 2H), 2.61-2.74 (m, 1H), 2.92-3.10 (m, 2H),3.39-3.55 (m, J=6.54, 6.54 Hz, 4H), 3.67 (dd, J=10.11, 6.94 Hz, 1H),3.87 (d, J=13.09 Hz, 1H), 4.01 (d, J=10.71 Hz, 1H), 5.25-5.38 (m, 1H),6.46 (d, J=8.33 Hz, 1H), 7.11 (d, J=7.14 Hz, 1H), 7.53 (dd, J=8.53, 7.34Hz, 1H), 7.92 (d, J=1.59 Hz, 1H), 8.03 (d, J=1.19 Hz, 1H); MS (ESI) m/z471.1 (M+H)⁺.

Example 62(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,4-difluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 110, substituting 2,4-difluorobenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃) δ ppm0.89-0.98 (m, 4H), 1.75-1.89 (m, 1H), 1.91-2.03 (m, 2H), 2.28-2.60 (m,4H), 2.68-2.82 (m, 1H), 2.95-3.05 (m, 1H), 3.67 (dd, J=10.17, 6.78 Hz,1H), 3.80 (dd, J=10.51, 1.36 Hz, 1H), 3.94 (d, J=10.85 Hz, 1H),5.24-5.37 (m, 1H), 6.90-7.05 (m, 2H), 7.82-7.92 (m, 1H), 7.92 (d, J=1.36Hz, 1H), 8.02 (d, J=1.36 Hz, 1H); MS (ESI) m/z 437.0 (M+H)⁺.

Example 63(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 58, substituting 2-bromo-4-(trifluoromethyl)pyridine for2-bromo-6-tert-butylpyridine. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.87-0.99(m, 4H), 1.76-1.91 (m, 1H), 1.92-2.04 (m, 2H), 2.35 (dd, J=10.17, 5.09Hz, 1H), 2.39-2.60 (m, 2H), 2.59-2.69 (m, 1H), 2.90-3.07 (m, 2H), 3.68(dd, J=10.17, 6.78 Hz, 1H), 3.87-3.95 (m, 1H), 4.01-4.11 (m, 1H),5.25-5.37 (m, 1H), 7.71 (dd, J=4.92, 0.85 Hz, 1H), 7.92 (d, J=1.36 Hz,1H), 8.03 (d, J=1.36 Hz, 1H), 8.14-8.18 (m, J=0.68 Hz, 1H), 8.90 (d,J=4.75 Hz, 1H); MS (ESI) m/z 470.0 (M+H)⁺.

Example 643-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-5-(trifluoromethyl)benzonitrileExample 64A(7R,8aS)-2-{[3-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 57, substituting 3-bromo-5-(trifluoromethyl)benzene-1-sulfonylchloride for 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride. ¹H NMR(300 MHz, CDCl₃) δ ppm 0.89-1.00 (m, 4H), 1.75-1.90 (m, 1H), 1.91-2.05(m, 2H), 2.16 (t, J=10.51 Hz, 1H), 2.34 (dd, J=10.31, 5.16 Hz, 1H),2.39-2.64 (m, 3H), 2.98-3.08 (m, 1H), 3.66 (dd, J=10.31, 6.74 Hz, 1H),3.74-3.81 (m, 1H), 3.86-3.98 (m, J=9.52 Hz, 1H), 5.23-5.36 (m, 1H), 7.92(d, J=1.59 Hz, 1H), 7.93 (s, 1H), 7.98 (s, 1H), 8.03 (d, J=1.59 Hz, 1H),8.08 (s, 1H).

Example 64B3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-5-(trifluoromethyl)benzonitrile

To a solution of the product from Example 64A (30 mg, 0.055 mmol) inN,N-dimethylformamide (0.3 mL) was added copper(I) cyanide (10 mg, 0.11mmol), and the resulting mixture was stirred at 130° C. for 16 hours.The cooled mixture was partitioned between water and ethyl acetate (3×),and the combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel using a solvent gradient of 0-60% ethylacetate in hexanes to give the title compound. ¹H NMR (300 MHz, CDCl₃) δppm 0.87-1.00 (m, 4H), 1.74-1.90 (m, 1H), 1.91-2.07 (m, 2H), 2.19 (t,J=10.34 Hz, 1H), 2.34 (dd, J=10.17, 5.09 Hz, 1H), 2.39-2.63 (m, 3H),2.98-3.10 (m, 1H), 3.66 (dd, J=10.17, 6.78 Hz, 1H), 3.80 (dd, J=10.17,1.70 Hz, 1H), 3.88-3.99 (m, 1H), 5.24-5.36 (m, 1H), 7.92 (d, J=1.36 Hz,1H), 8.03 (d, J=1.36 Hz, 1H), 8.11-8.14 (m, J=1.02 Hz, 1H), 8.17-8.26(m, J=4.07, 1.02 Hz, 2H); MS (ESI) m/z 494.0 (M+H)⁺.

Example 654-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-2-(trifluoromethyl)benzonitrile

The title compound was prepared using the procedure described forExample 64, substituting 4-bromo-3-(trifluoromethyl)benzene-1-sulfonylchloride for 3-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹HNMR (300 MHz, CDCl₃) δ ppm 0.87-1.00 (m, 4H), 1.72-1.90 (m, 1H),1.91-2.07 (m, 2H), 2.18 (t, J=10.31 Hz, 1H), 2.34 (dd, J=9.92, 5.16 Hz,1H), 2.39-2.63 (m, 3H), 2.97-3.08 (m, 1H), 3.66 (dd, J=10.31, 6.74 Hz,1H), 3.76-3.83 (m, 1H), 3.89-3.99 (m, 1H), 5.22-5.36 (m, 1H), 7.91 (d,J=1.59 Hz, 1H), 8.01-8.10 (m, 3H), 8.13-8.17 (m, J=0.79 Hz, 1H); MS(ESI) m/z 494.0 (M+H)⁺.

Example 66(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 57, substituting 6-(trifluoromethyl)pyridine-2-sulfonyl chloridefor 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride. ¹H NMR (300 MHz,CDCl₃) δ ppm 0.90-0.98 (m, 4H), 1.76-2.07 (m, 3H), 2.25-2.85 (m, 4H),2.94-3.19 (m, 2H), 3.58-3.80 (m, 1H), 3.93 (d, J=12.7 Hz, 1H), 4.07 (d,J=11.5 Hz, 1H), 5.34 (q, J=5.9 Hz, 1H), 7.82-7.90 (m, 1H), 7.93 (d,J=1.2 Hz, 1H), 8.03 (d, J=1.2 Hz, 1H), 8.10-8.14 (m, 2H); MS (ESI) m/z470.1 (M+H)⁺.

Example 67(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 57, substituting 5-(trifluoromethyl)pyridine-2-sulfonyl chloridefor 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride. ¹H NMR (300 MHz,CDCl₃) δ ppm 0.83-1.03 (m, 4H), 1.75-1.91 (m, 1H), 1.92-2.05 (m, 2H),2.29-2.73 (m, 4H), 2.88-3.10 (m, 2H), 3.68 (dd, J=9.8, 6.8 Hz, 1H),3.84-3.96 (m, 1H), 4.00-4.11 (m, J=8.8, 2.0 Hz, 1H), 5.24-5.38 (m, 1H),7.92 (d, J=1.4 Hz, 1H), 8.03 (d, J=1.4 Hz, 1H), 8.05-8.11 (m, 1H),8.14-8.20 (m, 1H), 8.96 (d, J=1.4 Hz, 1H); MS (ESI) m/z 470.0 (M+H)⁺.

Example 682-chloro-5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile

The title compound was prepared using the procedure described forExample 57, substituting 4-chloro-3-cyanobenzene-1-sulfonyl chloride for3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride. ¹H NMR (300 MHz,CDCl₃) δ ppm 0.90-0.98 (m, 4H), 1.70-1.88 (m, 1H), 1.91-2.04 (m, 2H),2.17 (t, J=10.5 Hz, 1H), 2.33 (dd, J=9.9, 5.2 Hz, 1H), 2.38-2.63 (m,3H), 3.01 (d, J=10.3 Hz, 1H), 3.65 (dd, J=9.9, 6.7 Hz, 1H), 3.76 (d,J=10.3 Hz, 1H), 3.91 (d, J=9.9 Hz, 1H), 5.18-5.43 (m, 1H), 7.51 (d,J=8.3 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.99 (dd, J=8.3, 2.8 Hz, 1H),8.03 (d, J=1.6 Hz, 1H), 8.77 (d, J=2.4 Hz, 1H); MS (ESI) m/z 436.0(M+H)⁺.

Example 69(7R,8aS)-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-2-{[6-(trifluoromethyl)-pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazineExample 69A(7R,8aS)-2-benzyl-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

To a solution of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol(Example 19D, 0.103 g, 0.443 mmol) in dimethyl sulfoxide (4 mL) wasadded a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran(0.665 mL, 0.665 mmol), and the resulting suspension was stirred at roomtemperature for 5 minutes. 5-Fluoro-2-(trifluoromethyl)pyridine (0.137g, 0.829 mmol) was added, and the reaction mixture was stirred at roomtemperature for 48 hours. The mixture was partitioned between ethylacetate and water, and the organic extract was dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. Purification bycolumn chromatography on silica gel using a solvent gradient of 0-95%ethyl acetate in hexane gave the titled compound. MS (APCI) m/z 378.4(M+H)⁺.

Example 69B(7R,8aS)-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]-pyrazine

The product from Example 69A (92 mg, 0.244 mmol) was subject to theprocedure described for Example 27B to give the title compound. MS(APCI) m/z 288.3 (M+H)⁺.

Example 69C(7R,8aS)-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-2-{[6-(trifluoromethyl)-pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The product from Example 69B (48 mg, 0.167 mmol) was subjected to theprocedure described in Example 27C, substituting6-(trifluoromethyl)pyridine-2-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titledcompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.78-1.94 (m, 1H), 1.95-2.07 (m,1H), 2.41-2.68 (m, 3H), 2.75 (t, J=10.9 Hz, 1H), 2.97-3.17 (m, 2H), 3.69(dd, J=9.7, 6.5 Hz, 1H), 3.89-4.00 (m, 1H), 4.09 (dd, J=11.5, 2.0 Hz,1H), 4.80-5.01 (m, 1H), 7.21 (dd, J=8.7, 2.4 Hz, 1H), 7.56-7.64 (m, 1H),7.81-7.91 (m, 1H), 8.09-8.16 (m, 2H), 8.32 (d, J=2.8 Hz, 1H); MS (ESI)m/z 497.0 (M+H)⁺.

Example 70(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of the product from Example 27B (28 mg, 0.11 mmol) indichloromethane (1 mL) was added triethylamine (0.023 mL, 0.164 mmol)and 6-morpholinopyridine-3-sulfonyl chloride (32 mg, 0.120 mmol), andthe resulting mixture was stirred at room temperature for 4 hours. Themixture was partitioned between water and dichloromethane (3×), and thecombined organic layers were concentrated in vacuo The crude product waspurified by column chromatography on C-18 silica gel using a solventgradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid).Fractions containing the pure product were pooled and concentrated byevaporation to give the title compound as a trifluoroacetic acid salt.¹H NMR (300 MHz, CDCl₃) δ ppm 0.86-1.09 (m, 4H), 1.91-2.10 (m, 1H),2.31-3.49 (m, 11H), 3.64-3.73 (m, 4H), 3.79-3.87 (m, 4H), 5.44-5.65 (m,1H), 6.63 (d, J=9.2 Hz, 1H), 7.70 (dd, J=9.2, 2.7 Hz, 1H), 7.94 (d,J=1.4 Hz, 1H), 8.10 (d, J=1.4 Hz, 1H), 8.51 (d, J=2.7 Hz, 1H); MS (ESI)m/z 487.1 (M+H)⁺.

Example 71(7R,8aS)-2-[(5-tert-butyl-2-methoxyphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting5-tert-butyl-2-methoxybenzene-1-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃) δ ppm0.92-1.01 (m, 4H), 1.31 (s, 9H), 1.91-2.08 (m, 2H), 2.25-2.57 (m, 2H),2.75-3.81 (m, 7H), 3.92 (s, 3H), 3.94-4.60 (m, 3H), 5.46-5.64 (m, 1H),6.97 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.7, 2.8 Hz, 1H), 7.87 (d, J=2.4 Hz,1H), 7.93 (d, J=1.6 Hz, 1H), 8.08 (d, J=1.2 Hz, 1H); MS (ESI) m/z 487.1(M+H)⁺.

Example 72(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-methyl-2-thienyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting5-methylthiophene-2-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃) δ ppm0.92-1.02 (m, 4H), 1.93-2.06 (m, 2H), 2.30-2.51 (m, 3H), 2.55 (s, 3H),2.79-4.55 (m, 7H), 5.46-5.59 (m, 1H), 6.84 (dd, J=3.8, 1.0 Hz, 1H), 7.39(d, J=4.0 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H); MS(ESI) m/z 421.0 (M+H)⁺.

Example 73(7R,8aS)-2-[(5-bromopyridin-3-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 27C, substituting 5-bromopyridine-3-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃)δ ppm 0.87-1.02 (m, 4H), 1.74-2.67 (m, H), 3.03 (d, J=11.1 Hz, 1H), 3.66(dd, J=9.9, 6.7 Hz, 1H), 3.78 (d, J=10.7 Hz, 1H), 3.93 (d, J=10.3 Hz,1H), 5.30 (q, J=6.1 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 8.03 (d, J=1.2 Hz,1H), 8.18 (t, J=2.2 Hz, 1H), 8.89 (t, J=2.2 Hz, 2H); MS (ESI) m/z 479.9(M+H)⁺.

Example 74(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-cyclopropylpyridin-3-yl)sulfonyl]octahydropyrrolo[1,2-a]pyrazine

A suspension of the product from Example 73 (21 mg, 0.044 mmol),cyclopropylboronic acid (4.9 mg, 0.057 mmol), tricyclohexylphosphine(1.2 mg, 4.39 μmol) and tribasic potassium phosphate (33 mg, 0.154 mmol)in toluene (0.5 mL) and water (0.100 mL) was degassed by bubbling withN₂ for 10 minutes. Palladium(II) acetate (0.49 mg, 2.2 μmol) was addedand the mixture was further degassed with N₂ for 15 minutes, and thereaction vessel was sealed and the mixture was stirred at 100° C. for3.5 hours. The cooled mixture was diluted with ethyl acetate and washedwith water. The organic extract was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a crude product that waspurified by column chromatography on C-18 silica gel using a solventgradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid).Fractions containing the pure product were pooled and concentrated byevaporation to give the title compound as a trifluoroacetic acid salt.¹H NMR (300 MHz, CDCl₃) δ ppm 0.80-0.89 (m, 2H), 0.92-1.02 (m, 4H),1.14-1.23 (m, 2H), 1.91-2.09 (m, 3H), 2.91-3.38 (m, J=10.3 Hz, 4H),3.49-3.73 (m, 2H), 3.71-3.94 (m, 1H), 3.93-4.14 (m, 1H), 4.14-4.38 (m,1H), 5.45-5.63 (m, 1H), 7.66 (t, J=2.2 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H),8.09 (d, J=1.2 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H);MS (ESI) m/z 442.0 (M+H)⁺.

Example 75(7R,8aS)-2-[(6-chloropyridin-3-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared using the procedure described forExample 27C, substituting 6-chloropyridine-3-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃)δ ppm 0.90-0.98 (m, 4H), 1.70-1.88 (m, 1H), 1.91-2.04 (m, 2H), 2.17 (t,J=10.5 Hz, 1H), 2.33 (dd, J=9.9, 5.2 Hz, 1H), 2.38-2.63 (m, 3H), 3.01(d, J=10.3 Hz, 1H), 3.65 (dd, J=9.9, 6.7 Hz, 1H), 3.76 (d, J=10.3 Hz,1H), 3.91 (d, J=9.9 Hz, 1H), 5.18-5.43 (m, 1H), 7.51 (d, J=8.3 Hz, 1H),7.92 (d, J=1.2 Hz, 1H), 7.99 (dd, J=8.3, 2.8 Hz, 1H), 8.03 (d, J=1.6 Hz,1H), 8.77 (d, J=2.4 Hz, 1H); MS (ESI) m/z 436.0 (M+H)⁺.

Example 765-{[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}-1,3-benzoxazole

The title compound was prepared according to the procedure described inExample 41, substituting benzo[d]oxazol-5-ol for4-(trifluoromethoxy)phenol. Purification by chromatography on silica gel(first with 4% CH₃OH/CH₂Cl₂, then a second time with 40% to 100% ethylacetate/hexanes) afforded the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 8.65 (s, 1H), 8.18-8.03 (m, 2H), 7.98 (s, 1H), 7.92 (t, J=7.8,1H), 7.62 (d, J=8.9, 1H), 7.22 (d, J=2.5, 1H), 6.90 (dd, J=8.9, 2.5,1H), 4.95-4.84 (m, 1H), 3.88-3.78 (m, 1H), 3.73-3.60 (m, 1H), 3.11-2.94(m, 2H), 2.59-2.38 (m, 3H), 2.24-2.03 (m, 3H), 1.46-1.29 (m, 1H); MS(ESI+) m/z 468 (M+H)⁺.

Example 77(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

Diisopropyl azodicarboxylate (0.085 mL, 0.440 mmol) was added dropwiseto a mixture of Example 19 (140 mg, 0.400 mmol),6-(trifluoromethyl)pyridin-3-ol (71 mg, 0.44 mmol), and polymersupported triphenylphosphine (3 mmol/g, 147 mg, 0.440 mmol) in anhydroustetrahydrofuran (1.5 mL) at ambient temperature. The reaction mixturewas stirred for 18 hours and then filtered into a mixture of ethylacetate and H₂O. The separated organic phase was washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. Chromatography onsilica gel (50% ethyl acetate/hexanes) afforded the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 8.33 (d, J=2.8, 1H), 8.14 (d, J=7.9, 1H),8.08 (d, J=7.9, 1H), 7.98 (s, 1H), 7.91 (t, J=7.8, 1H), 7.80 (d, J=8.7,1H), 7.49 (dd, J=8.7, 2.7, 1H), 5.07-4.98 (m, 1H), 3.88-3.79 (m, 1H),3.73-3.63 (m, 1H), 3.12-2.96 (m, 2H), 2.61-2.38 (m, 3H), 2.25-2.04 (m,3H), 1.44-1.31 (m, 1H); MS (ESI+) m/z 496 (M+H)⁺.

Example 782-methyl-6-{[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}-1,3-benzoxazole

To a mixture of Example 19 (138 mg, 0.394 mmol),2-methylbenzo[d]oxazol-6-ol (88 mg, 0.59 mmol), and polymer supportedtriphenylphosphine (3 mmol/g, 197 mg, 0.591 mmol) in anhydroustetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (0.11mL, 0.59 mmol) dropwise via syringe. The reaction mixture was stirredfor 18 hours, then filtered through glass wool, and the filtrate wasconcentrated in vacuo. The residue was chromatographed on silica gel(50% ethyl acetate/hexanes) to afford the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.14 (d, J=8.6, 1H), 8.12-8.05 (m, 1H), 7.98 (bs,1H), 7.92 (t, J=7.8, 1H), 7.47 (d, J=8.6, 1H), 7.15 (d, J=2.3, 1H), 6.79(dd, J=8.6, 2.4, 1H), 4.93-4.83 (m, 1H), 3.83 (bd, J=10.3, 1H), 3.67(bd, J=11.2, 1H), 3.09-2.97 (m, 2H), 2.81-2.60 (m, 1H), 2.54 (s, 3H),2.47-2.38 (m, 2H), 2.24-2.01 (m, 3H), 1.42-1.29 (m, 1H); MS (ESI+) m/z482 (M+H)⁺.

Example 79(7S,8aS)-7-(4-fluoro-3-methylphenoxy)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 78 substituting 4-fluoro-3-methylphenol for2-methylbenzo[d]oxazol-6-ol. Purification by chromatography (first bysilica gel; 15% to 50% ethyl acetate/hexanes and 0% to 5% CH₃OH/CH₂Cl₂,and then by reverse phase HPLC; Phenomenex® Luna® C8(2) 5 μm 100 Å AXIAcolumn (30×75 mm) with gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)) afforded thetitle compound as a trifluoroacetic acid salt. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 8.23-8.09 (m, J=16.8, 7.9, 2H), 8.04 (s, 1H), 7.97 (t, J=7.8, 1H),7.05 (t, J=9.1, 1H), 6.79 (dd, J=6.3, 3.0, 1H), 6.75-6.65 (m, J=8.8,1H), 5.10-4.94 (m, 1H), 4.57-2.58 (m, 14H), 1.85-1.39 (m, 1H); MS (ESI+)m/z 459 (M+H)⁺.

Example 80(7R,8aS)-7-[(5-methylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18, substituting Example 19 for Example 17 and2-bromo-5-methylpyrazine for 2-bromo-5-cyclopropylpyrazine. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.18-8.06 (m, 3H), 8.03 (d, J=0.8, 1H), 7.99 (s,1H), 7.92 (t, J=7.9, 1H), 5.25-5.15 (m, 1H), 3.88-3.79 (m, 1H),3.72-3.62 (m, 1H), 3.55 (dd, J=9.8, 6.8, 1H), 3.02-2.93 (m, 1H),2.45-2.30 (m, 5H), 2.30-2.23 (m, 1H), 2.19 (dd, J=9.8, 5.2, 1H), 2.08(t, J=10.6, 1H), 1.87 (ddd, J=13.6, 5.9, 1.6, 1H), 1.84-1.70 (m, 1H); MS(ESI+) m/z 443 (M+H)⁺.

Example 81(7R,8aS)-7-[(6-methylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18, substituting Example 19 for Example 17 and2-bromo-6-methylpyrazine for 2-bromo-5-cyclopropylpyrazine. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.18-8.04 (m, 4H), 7.99 (bs, 1H), 7.93 (t, J=7.9,1H), 5.29-5.18 (m, 1H), 3.88-3.79 (m, 1H), 3.71-3.62 (m, 1H), 3.57 (dd,J=9.9, 6.7, 1H), 3.06-2.95 (m, 1H), 2.42-2.15 (m, 7H), 2.09 (t, J=10.5,1H), 1.91 (ddd, J=13.6, 5.9, 1.9, 1H), 1.85-1.71 (m, 1H); MS (ESI+) m/z443 (M+H)⁺.

Example 82(7R,8aS)-7-{[6-chloro-5-(trifluoromethyl)pyridin-3-yl]oxy}-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

A solution of potassium t-butoxide, 1.0 M in tetrahydrofuran (0.57 mL,0.57 mmol) was added dropwise via syringe to a solution of Example 19(143 mg, 0.408 mmol) in anhydrous dimethyl sulfoxide (1.5 mL) at ambienttemperature. After stirring for 5 minutes, a solution of2-chloro-5-fluoro-3-(trifluoromethyl)pyridine (98 mg, 0.49 mmol) indimethyl sulfoxide (1 mL) was added. The reaction was allowed to proceedfor 6 days, and then the mixture was poured into H₂O. The product wasextracted with ethyl acetate, and the organic extract was washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography on silica gel (50% to 100% ethyl acetate/hexanes)afforded the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.41-8.36(m, 1H), 8.19-8.11 (m, 1H), 8.13-8.06 (m, 1H), 7.99 (d, J=1.8, 1H), 7.93(t, J=7.8, 1H), 7.81 (d, J=3.0, 1H), 5.12-5.01 (m, 1H), 3.88-3.80 (m,1H), 3.72-3.63 (m, 1H), 3.59 (dd, J=9.8, 6.6, 1H), 3.03-2.95 (m, 1H),2.44-2.16 (m, 4H), 2.08 (t, J=10.5, 1H), 2.01-1.74 (m, 2H); MS (ESI+)m/z 530 (M+H)⁺.

Example 83(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)-pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18, substituting Example 19 for Example 17 and2-bromo-5-(trifluoromethyl)-pyridine for 2-bromo-5-cyclopropylpyrazine.¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.58-8.53 (m, 1H), 8.18-8.02 (m, 3H),7.99 (bs, 1H), 7.92 (t, J=7.9, 1H), 7.00 (d, J=8.7, 1H), 5.38-5.27 (m,1H), 3.89-3.80 (m, 1H), 3.72-3.63 (m, 1H), 3.58 (dd, J=9.9, 6.7, 1H),3.06-2.95 (m, 1H), 2.45-2.16 (m, 4H), 2.09 (t, J=10.6, 1H), 1.97-1.87(m, 1H), 1.79 (ddd, J=13.7, 10.4, 8.2, 1H); MS (ESI+) m/z 496 (M+H)⁺.

Example 84(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 82, substituting 5-fluoro-2-(trifluoromethyl)pyridine for2-chloro-5-fluoro-3-(trifluoromethyl)pyridine. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 8.40 (d, J=2.8, 1H), 8.18-8.06 (m, 2H), 7.99 (bs, 1H), 7.93 (t,J=7.9, 1H), 7.82 (d, J=8.7, 1H), 7.55 (dd, J=8.7, 2.9, 1H), 5.06-4.95(m, 1H), 3.90-3.80 (m, 1H), 3.71-3.56 (m, 2H), 3.06-2.95 (m, 1H),2.46-2.19 (m, 4H), 2.08 (t, J=10.6, 1H), 1.96-1.75 (m, 2H); MS (ESI+)m/z 496 (M+H)⁺.

Example 856-{[(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}nicotinonitrile

The title compound was prepared according to the procedure described inExample 18, substituting Example 19 for Example 17 and6-bromonicotinonitrile for 2-bromo-5-cyclopropylpyrazine. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.66 (dd, J=2.3, 0.6, 1H), 8.18-8.11 (m, 2H), 8.09(d, J=7.9, 1H), 7.99 (bs, 1H), 7.92 (t, J=7.8, 1H), 6.99 (dd, J=8.7,0.8, 1H), 5.36-5.26 (m, 1H), 3.88-3.79 (m, 1H), 3.71-3.62 (m, 1H), 3.57(dd, J=9.9, 6.7, 1H), 3.07-2.94 (m, 1H), 2.45-2.16 (m, 4H), 2.13-2.04(m, 1H), 1.91 (ddd, J=13.6, 5.8, 1.8, 1H), 1.79 (ddd, J=13.6, 10.4, 8.0,1H); MS (ESI+) m/z 453 (M+H)⁺.

Example 865-{[(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}pyridine-2-carbonitrile

The title compound was prepared according to the procedure described inExample 82, substituting 5-fluoropicolinonitrile for2-chloro-5-fluoro-3-(trifluoromethyl)pyridine. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 8.41-8.37 (m, 1H), 8.14 (d, J=7.8, 1H), 8.09 (d, J=8.1, 1H),8.01-7.89 (m, 3H), 7.53 (dd, J=8.7, 2.9, 1H), 5.06-4.95 (m, 1H),3.89-3.80 (m, 1H), 3.71-3.64 (m, 1H), 3.60 (dd, J=9.8, 6.7, 1H),3.02-2.94 (m, 1H), 2.45-2.19 (m, 5H), 1.94-1.75 (m, 2H); MS (ESI+) m/z453 (M+H)⁺.

Example 87(7R,8aS)-7-[(6-bromopyridin-3-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 82, substituting 2-bromo-5-fluoropyridine for2-chloro-5-fluoro-3-(trifluoromethyl)pyridine. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 8.18-8.04 (m, 3H), 7.99 (bs, 1H), 7.93 (t, J=7.9, 1H), 7.53 (d,J=8.7, 1H), 7.34 (dd, J=8.7, 3.2, 1H), 4.94-4.83 (m, 1H), 3.89-3.80 (m,1H), 3.71-3.63 (m, 1H), 3.56 (dd, J=9.7, 6.7, 1H), 3.02-2.94 (m, 1H),2.43-2.16 (m, 4H), 2.07 (t, J=10.5, 1H), 1.92-1.70 (m, 2H); MS (ESI+)m/z 506/508 (M+H)⁺.

Example 88(7R,8aS)-7-[(6-cyclopropylpyridin-3-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

A solution of Example 87 (150 mg, 0.296 mmol) and[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride (2.0 mg, 2.9 μmol) in anhydrous tetrahydrofuran (0.3 mL) wasstirred at ambient temperature for 30 minutes. A solution ofcyclopropylzinc(II) bromide, 0.5 M in tetrahydrofuran (0.90 mL, 0.44mmol) was then added. The reaction was allowed to proceed for 20 hoursand then quenched by addition of 3 M HCl (0.5 mL). The crude productmixture was partitioned between ethyl acetate and 2 N NaOH solution. Theseparated organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Chromatography on silica gel (50%to 100% ethyl acetate/hexanes) yielded the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.18-8.02 (m, 3H), 7.99 (bs, 1H), 7.92 (t, J=7.9,1H), 7.23-7.13 (m, 2H), 4.86-4.76 (m, 1H), 3.90-3.78 (m, 1H), 3.73-3.61(m, 1H), 3.53 (dd, J=9.6, 6.7, 1H), 3.02-2.91 (m, 1H), 2.42-2.13 (m,4H), 2.11-1.94 (m, 2H), 1.89-1.67 (m, 2H), 0.90-0.73 (m, 4H). MS (ESI+)m/z 468 (M+H)⁺.

Example 89(7R,8aS)-7-[(5-bromopyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18, substituting Example 19 for Example 17 and2,5-dibromopyridine for 2-bromo-5-cyclopropylpyrazine. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.24 (dd, J=2.7, 0.6, 1H), 8.17-8.12 (m, 1H), 8.11-8.06(m, 1H), 7.98 (bs, 1H), 7.93 (d, J=7.9, 1H), 7.88 (dd, J=8.8, 2.5, 1H),6.80 (d, J=8.8, 1H), 5.25-5.15 (m, 1H), 3.87-3.79 (m, 1H), 3.71-3.62 (m,1H), 3.54 (dd, J=9.8, 6.7, 1H), 3.02-2.93 (m, 1H), 2.44-2.13 (m, 4H),2.08 (t, J=10.6, 1H), 1.87 (ddd, J=6.5, 5.9, 1.9, 1H), 1.75 (ddd,J=13.5, 10.3, 8.1, 1H). MS (ESI+) m/z 506/508 (M+H)⁺.

Example 90(7R,8aS)-7-[(5-cyclopropylpyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 88, substituting Example 89 for Example 87. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.18-8.11 (m, 1H), 8.13-8.05 (m, 1H), 7.98 (bs, 1H),7.96-7.87 (m, 2H), 7.34 (dd, J=8.5, 2.5, 1H), 6.67 (d, J=8.5, 1H),5.25-5.13 (m, 1H), 3.87-3.78 (m, 1H), 3.72-3.62 (m, 1H), 3.53 (dd,J=9.8, 6.7, 1H), 3.00-2.93 (m, 1H), 2.45-2.01 (m, 5H), 1.92-1.79 (m,2H), 1.80-1.66 (m, 1H), 0.94-0.84 (m, 2H), 0.65-0.57 (m, 2H); MS (ESI+)m/z 468 (M+H)⁺.

Example 91(7R,8aS)-7-[(6-bromopyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyaolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 82, substituting 2-bromo-6-fluoropyridine for2-chloro-5-fluoro-3-(trifluoromethyl)pyridine. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 8.14 (dd, J=7.9, 1.7, 1H), 8.13-8.05 (m, 1H), 7.99 (s, 1H), 7.92(t, J=7.8, 1H), 7.65 (dd, J=8.2, 7.5, 1H), 7.21 (dd, J=7.5, 0.6, 1H),6.84 (dd, J=8.2, 0.6, 1H), 5.22-5.11 (m, 1H), 3.88-3.80 (m, 1H),3.71-3.62 (m, 1H), 3.55 (dd, J=9.8, 6.7, 1H), 3.07-2.95 (m, 1H),2.45-2.14 (m, 4H), 2.09 (t, J=10.6, 1H), 1.89 (ddd, J=13.5, 5.9, 1.7,1H), 1.77 (ddd, J=13.6, 10.3, 8.1, 1H); MS (ESI+) m/z 506/508 (M+H)⁺.

Example 92(7R,8aS)-7-[(6-cyclopropylpyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 88, substituting Example 91 for Example 87. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.18-8.06 (m, 2H), 7.99 (d, J=1.7, 1H), 7.93 (t, J=7.9,1H), 7.51 (dd, J=8.2, 7.3, 1H), 6.88 (dd, J=7.3, 0.8, 1H), 6.49 (dd,J=8.1, 0.8, 1H), 5.19-5.07 (m, 1H), 3.88-3.79 (m, 1H), 3.71-3.62 (m,1H), 3.49 (dd, J=9.7, 6.7, 1H), 3.02-2.94 (m, 1H), 2.43-1.94 (m, 6H),1.85 (ddd, J=13.5, 6.0, 1.9, 1H), 1.80-1.65 (m, 1H), 0.92-0.83 (m, 4H);MS (ESI+) m/z 468 (M+H)⁺.

Example 91(7R,8aS)-7-[(5-bromo-1,3-thiazol-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 18, substituting Example 19 for Example 17 and2,5-dibromothiazole for 2-bromo-5-cyclopropylpyrazine. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.14 (bd, J=7.9, 1H), 8.08 (bd, J=8.0, 1H), 7.98 (bs,1H), 7.92 (t, J=7.9, 1H), 7.30 (s, 1H), 5.28-5.16 (m, 1H), 3.88-3.78 (m,1H), 3.71-3.61 (m, 1H), 3.55 (dd, J=10.2, 6.8, 1H), 3.02-2.92 (m, 1H),2.44-2.20 (m, 4H), 2.13-1.93 (m, 2H), 1.83-1.68 (m, 1H); MS (ESI+) m/z512/514 (M+H)⁺.

Example 94(7R,8aS)-7-[(5-cyclopropyl-1,3-thiazol-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 88, substituting Example 93 for Example 87. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.18-8.10 (m, 1H), 8.12-8.05 (m, 1H), 7.98 (bs, 1H), 7.92(t, J=7.9, 1H), 6.86 (d, J=1.1, 1H), 5.21-5.10 (m, 1H), 3.87-3.78 (m,1H), 3.70-3.62 (m, 1H), 3.53 (dd, J=10.1, 6.7, 1H), 3.01-2.92 (m, 1H),2.43-2.16 (m, 4H), 2.06 (t, J=10.6, 1H), 1.99-1.87 (m, 2H), 1.80-1.65(m, 1H), 0.95-0.84 (m, 2H), 0.64-0.55 (m, 2H); MS (ESI+) m/z 474 (M+H)⁺.

Example 95(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3-difluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 27C, substituting 2,3-difluorobenzene-1-sulfonyl chloride for2-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (300 MHz,DMSO-d₆) 8 ppm 8.11 (s, 2H), 7.90-7.76 (m, 1H), 7.65-7.55 (m, 1H), 7.46(tdd, J=8.2, 4.6, 1.4, 1H), 5.22 (dd, J=12.5, 5.8, 1H), 3.90-3.73 (m,1H), 3.71-3.50 (m, 2H), 3.06-2.94 (m, 1H), 2.71-2.58 (m, 1H), 2.41-2.16(m, 4H), 2.10 (tt, J=8.2, 4.9, 1H), 1.97-1.72 (m, 2H), 0.99-0.74 (m,4H); MS (ESI+) m/z 437 (M+H)⁺.

Example 96(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-fluoro-2-(piperidin-1-yl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

A reaction vial charged with Example 95 (98 mg, 0.22 mmol), piperidine(0.044 mL, 0.449 mmol), and anhydrous dimethyl sulfoxide (1 mL) wasplaced in a heating block at 105° C. for 3.5 hours. The reaction mixturewas cooled to ambient temperature and poured into H₂O. The product wasextracted with ethyl acetate, and the organic extract was washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography on silica gel (50% ethyl acetate/hexanes) yielded thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.13-8.10 (m, 2H),7.71-7.63 (m, 1H), 7.54 (ddd, J=12.6, 8.2, 1.6, 1H), 7.40 (td, J=8.1,5.0, 1H), 5.30-5.18 (m, 1H), 3.91-3.83 (m, 1H), 3.75-3.65 (m, 1H), 3.59(dd, J=9.8, 6.8, 1H), 3.05-2.96 (m, 5H), 2.75-2.62 (m, 1H), 2.44-2.16(m, 4H), 2.15-2.04 (m, 1H), 1.96-1.50 (m, 8H), 0.98-0.87 (m, 2H),0.87-0.77 (m, 2H); MS (ESI+) m/z 502 (M+H)⁺.

Example 97(7R,8aS)-7-[(4-tert-butylbenzyl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of Example 19 (0.033 g, 0.094 mmol) in tetrahydrofuran (1mL) was added a 1.0 M solution of potassium tert-butoxide intetrahydrofuran (0.118 mL, 0.118 mmol). The resulting mixture wasstirred for 10 minutes, and 1-(bromomethyl)-4-tert-butylbenzene (0.019ml, 0.104 mmol) was added. The resulting mixture was stirred at roomtemperature for 16 hours. The mixture was partitioned between water andethyl acetate. The organic extract was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on C18 reversed-phase chromatography using a solventgradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid).The title compound was obtained as a trifluoroacetic acid salt. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.27 (s, 9H), 2.15 (s, 2H), 2.84-3.23 (m, 2H),3.76-4.32 (m, 3H), 4.34-4.46 (m, 2H), 7.20-7.29 (m, 2H), 7.33-7.39 (m,2H), 7.95 (t, J=7.9 Hz, 1H), 8.04 (s, 1H), 8.15 (dd, J=14.1, 8.1 Hz,2H); MS (ESI+) m/z 497 (M+H)⁺.

Example 98(7R,8aS)-7-{[4-(trifluoromethoxy)benzyl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 97, substituting1-(bromomethyl)-4-(trifluoromethoxy)benzene for1-(bromomethyl)-4-tert-butylbenzene. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.42-2.24 (m, 2H), 3.65-4.36 (m, J=73.8 Hz, 4H), 4.40-4.55 (m, 2H),7.29-7.39 (m, 2H), 7.41-7.51 (m, 2H), 7.95 (t, J=7.7 Hz, 1H), 8.03 (s,1H), 8.15 (dd, J=13.9, 7.9 Hz, 2H); MS (ESI+) m/z 525 (M+H)⁺.

Example 99(7R,8aS)-7-{[4-(trifluoromethyl)benzyl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 97, substituting1-(bromomethyl)-4-(trifluoromethyl)benzene for1-(bromomethyl)-4-tert-butylbenzene. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.51-2.22 (m, 3H), 3.56-4.41 (m, 5H), 4.46-4.63 (m, 2H), 7.55 (d, J=7.8Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.95 (t, J=7.8 Hz, 1H), 8.03 (s, 1H),8.15 (dd, J=13.2, 7.8 Hz, 2H); MS (ESI+) m/z 509 (M+H)⁺.

Example 100(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(1,1-difluoroethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To1-(4-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}phenyl)ethanone(Example 48, 120 mg, 0.271 mmol) in dichloromethane (0.5 mL) was addedbis(2-methoxyethyl)aminosulfur trifluoride (300 mg, 1.356 mmol). Themixture was heated at 80° C. for 18 hours, and then 1 N Na₂CO₃ (15 mL)was added. The mixture was extracted with dichloromethane (2×30 mL), andthe combined organic phases were concentrated. The residue was purifiedby chromatography on silica gel (hexane/ethyl acetate=1:1) to give thetitle compound (25 mg, 20% yield) as a gummy solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.86-1.25 (m, 4H), 1.82-2.15 (m, 7H), 2.92 (m, 1H), 2.32(m, 1H), 3.45-3.73 (m, 4H), 5.21 (m, 1H), 7.84 (m, 4H), 8.11 (s, 2H); MS(ESI) m/z 467 (M+H)⁺.

Example 101(7R,8aS)-7-[(5-cyclobutylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The procedures for Example 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting2-bromo-5-cyclobutylpyrazine for 2-bromo-5-cyclopropylpyrazine to givethe title compound 64% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.87 (m, 3H), 2.05 (m, 3H), 2.23 (m, 5H), 2.38 (m, 2H), 2.99 (m,1H), 3.58 (m, 3H), 3.84 (m, 1H), 5.21 (m, 1H), 7.95 (m, 2H), 8.05 (m,2H), 8.15 (s, 2H); MS (ESI) m/z 484 (M+H)⁺.

Example 102(7R,8aS)-7-[(5-cyclobutylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The procedures for Example 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol, substituting2-bromo-5-cyclobutylpyrazine for 2-bromo-5-cyclopropylpyrazine, andsubstituting 4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (64% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87(m, 3H), 2.05 (m, 3H), 2.23 (m, 5H), 2.38 (m, 2H), 2.99 (m, 1H), 3.58(m, 3H), 3.84 (m, 1H), 5.21 (m, 1H), 8.03 (m, 5H), 8.24 (s, 1H); MS(ESI) m/z 484 (M+H)⁺.

Example 103(7R,8aS)-2-(biphenyl-3-ylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting biphenyl-3-sulfonylchloride for 6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.77-0.86 (m, 2H), 0.90-1.00 (m, 2H), 1.88-2.35 (m, 3H),3.12-3.44 (m, 4H), 3.69-4.28 (m, 5H), 5.33 (s, 1H), 7.41-7.60 (m, 3H),7.71-7.85 (m, 4H), 7.95 (s, 1H), 8.03-8.11 (m, 1H), 8.12-8.18 (m, 2H);MS (ESI) m/z 477 (M+H)⁺.

Example 104(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-isopropylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting4-isopropylbenzene-1-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, DMSO-d₆) δppm 0.77-0.87 (m, 2H), 0.90-1.01 (m, 2H), 1.24 (d, J=6.7 Hz, 6H),2.02-2.33 (m, 3H), 2.91-3.17 (m, 2H), 3.63-4.64 (m, J=3.2 Hz, 8H), 5.39(d, J=6.7 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.68-7.76 (m, 2H), 8.16 (d,J=4.0 Hz, 2H); MS (ESI) m/z 443 (M+H)⁺.

Example 105(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-methoxyphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting3-methoxybenzene-1-sulfonyl chloride for 6-morpholinopyridine-3-sulfonylchloride. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.75-0.86 (m, 2H), 0.89-1.03(m, 2H), 2.02-2.35 (m, 3H), 3.57-4.49 (m, 12H), 5.39 (s, 1H), 7.20-7.26(m, 1H), 7.31-7.39 (m, 2H), 7.62 (t, J=8.1 Hz, 1H), 8.09-8.20 (m, 2H);MS (ESI) m/z 431 (M+H)⁺.

Example 106(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-methoxy-3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting4-methoxy-3-(trifluoromethyl)benzene-1-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, DMSO-d₆) δppm 0.77-0.86 (m, 2H), 0.90-1.00 (m, 2H), 1.99-2.33 (m, 3H), 3.24-3.43(m, 4H), 3.80-3.96 (m, J=7.5 Hz, 2H), 4.03 (s, 3H), 5.35 (s, 1H), 7.56(d, J=8.8 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 8.07 (dd, J=8.8, 2.4 Hz, 1H),8.12-8.19 (m, 2H); MS (ESI) m/z 499 (M+H)⁺.

Example 107(7R,8aS)-2-[(3-tert-butylphenyl)sulfonyl]octahydropyrrolo[1,2-a]pyrazin-7-ol

The procedure for making Example 19 was used substituting3-(tert-butyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (93% yield). MS (ESI) m/z 338 (M+H)⁺.

Example 1081-(3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}phenyl)ethanone

To(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine(1 mmol, Example 27B) and triethylamine (1.5 mmol) in dichloromethane (6mL) was added 3-acetylbenzene-1-sulfonyl chloride (1.1 mmol) indichloromethane (2 mL). The mixture was stirred at room temperature for18 hours. The mixture was concentrated, and the residue was purified bychromatography on silica gel (ethyl acetate) to give the title compound(370 mg) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (m, 2H), 0.91(m, 2H), 1.75 (m, 1H), 1.89 (m, 1H), 2.06 (m, 2H), 2.19 (m, 2H), 2.30(m, 3H), 3.67 (s, 2H), 2.97 (m, 1H), 3.54 (m, 1H), 3.65 (m, 1H), 3.80(m, 1H), 5.19 (m, 1H), 7.83 (m, 1H), 8.00 (m, 1H), 8.15 (m, 3H), 8.30(m, 1H); MS (ESI) m/z 444 (M+H)⁺.

Example 109(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(1,1-difluoroethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To1-(3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}phenyl)ethanone(221 mg, 0.5 mmol, Example 108) in dichloromethane (0.5 mL) was addedbis(2-methoxyethyl)aminosulfur trifluoride (498 mg, 2.25 mmol). Themixture was heated at 60° C. for 18 hours. Then 1 N Na₂CO₃ (25 mL) wasadded. The mixture was extracted with dichloromethane (2×30 mL). Theorganic phase was concentrated, and the residue was purified bychromatography on silica gel (hexane/ethyl acetate=1:1) to give thetitle compound (18 mg, 8% yield) as a gummy solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.85 (m, 3H), 1.82 (m, 2H), 2.02 (m, 4H), 2.16 (m, 2H),2.35 (m, 2H), 3.11 (m, 2H), 3.54 (m, 2H), 5.21 (m, 1H), 7.92 (m, 2H),7.81 (m, 2H), 8.11 (m, 2H); MS (ESI) m/z 467 (M+H)⁺.

Example 110(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine

To a solution of the product from Example 27B (20 mg, 0.077 M) inpyridine (1.0 mL) was added 4-methylbenzene-1-sulfonyl chloride (18 mg,0.092 mmol), and the resulting mixture was shaken at room temperatureovernight. The reaction mixture was concentrated to dryness, and theresidue was purified by C18 reversed-phase chromatography using asolvent gradient of 0-100% acetonitrile in water (0.1% trifluoroaceticacid) to give the title compound as a trifluoroacetic acid salt (18.5mg, 46%). ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.09(dd, J=12.82, 1.53 Hz, 2H) 7.69 (d, J=8.24 Hz, 2H) 7.48 (d, J=7.93 Hz,2H) 5.39-5.53 (m, 1H) 3.89 (dd, J=12.66, 6.26 Hz, 1H) 3.75 (dd, J=13.12,3.36 Hz, 1H) 3.59-3.69 (m, 1H) 3.55 (d, J=12.82 Hz, 1H) 3.39-3.47 (m,1H) 3.17-3.27 (m, 2H) 2.94-3.07 (m, 1H) 2.86 (dd, J=12.82, 9.16 Hz, 1H)2.43 (s, 3H) 2.07-2.34 (m, 3H) 0.91-1.02 (m, 2H) 0.77-0.87 (m, 2H); MS(ESI) m/z 415 (M+H)⁺.

Example 111(7R,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine

A mixture of(7S,8aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol(Example 17, 103 mg, 0.294 mmol), 5-cyclopropylpyrazin-2-ol (40 mg,0.294 mmol) and triphenylphosphine (154 mg, 0.588 mmol) intetrahydrofuran (1 mL) was stirred at room temperature for 1 hour. Then(E)-diisopropyl diazene-1,2-dicarboxylate (119 mg, 0.588 mmol) wasadded, and the reaction was continued at room temperature overnight. Thesolution was concentrated, and the residue was purified bychromatography on silica gel (ethyl acetate/hexane=3:2) to give thetitle compound (68 mg, 48% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.86 (m, 4H), 1.22 (m, 2H), 2.12 (m, 4H), 2.41 (m, 2H), 3.01 (m,2H), 3.67 (m, 1H), 3.83 (m, 1H), 5.25 (m, 1H), 7.94 (m, 1H), 8.03 (m,1H), 8.15 (m, 4H); MS (ESI) m/z 469 (M+H)⁺.

Example 112(7R,8aS)-2-{[3-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The procedures for Example 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting3-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (67% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87(m, 4H), 1.89 (m, 3H), 2.21 (m, 5H), 2.99 (m, 1H), 3.56 (m, 1H), 3.69(m, 1H), 3.85 (m, 1H), 5.21 (m, 1H), 7.99 (m, 1H), 8.11 (s, 1H), 8.23(s, 2H), 8.42 (m, 1H); MS (ESI) m/z 548 (M+H)⁺.

Example 113(7R,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

The procedures for Example 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting2-bromo-5-(prop-1-en-2-yl)pyrazine for 2-bromo-5-cyclopropylpyrazine togive the title compound (45% yield) as a solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.76 (s, 9H), 1.95 (m, 1H), 2.12 (m, 2H), 2.28 (m, 7H),2.96 (m, 1H), 3.59 (m, 2H), 3.80 (m, 1H), 5.24 (m, 2H), 5.85 (m, 1H),7.63 (m, 3H), 7.78 (m, 1H), 8.25 (s, 1H), 8.38 (m, 1H); MS (ESI) m/z 457(M+H)⁺.

Example 114(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting2,3-dihydrobenzofuran-5-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃) δ ppm0.87-1.06 (m, 4H) 1.93-2.08 (m, 2H) 2.38 (dd, J=13.68, 4.96 Hz, 2H)2.76-3.22 (m, 3H) 3.29 (t, J=8.72 Hz, 2H) 3.40-4.53 (m, 5H) 4.71 (t,J=8.92 Hz, 2H) 5.53 (s, 1H) 6.89 (d, J=9.12 Hz, 1H) 7.50-7.59 (m, 2H)7.93 (d, J=1.19 Hz, 1H) 8.09 (d, J=1.19 Hz, 1H); MS (ESI) m/z 443(M+H)⁺.

Example 115(7R,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The procedures for Example 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting2-bromo-5-(prop-1-en-2-yl)pyrazine for 2-bromo-5-cyclopropylpyrazine togive the title compound (77% yield) as a solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.93 (m, 1H), 2.11 (m, 4H), 2.24 (m, 2H), 2.38 (m, 2H),2.99 (m, 1H), 3.58 (m, 2H), 3.66 (m, 1H), 3.84 (m, 1H), 5.26 (m, 2H),5.85 (m, 1H), 7.95 (m, 2H), 8.10 (m, 2H), 8.26 (m, 1H), 8.38 (m, 1H); MS(ESI) m/z 469 (M+H)⁺.

Example 116(7R,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The procedures for Example 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol, substituting2-bromo-5-(prop-1-en-2-yl)pyrazine for 2-bromo-5-cyclopropylpyrazine,and substituting 4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (85% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.93(m, 1H), 2.11 (m, 4H), 2.24 (m, 2H), 2.38 (m, 2H), 2.99 (m, 1H), 3.58(m, 2H), 3.66 (m, 1H), 3.84 (m, 1H), 5.26 (m, 2H), 5.85 (m, 1H), 7.98(m, 2H), 8.05 (m, 2H), 8.26 (m, 1H), 8.39 (m, 1H); MS (ESI) m/z 469(M+H)⁺.

Example 117(7R,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-[(5-isopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine

(7R,8aS)-2-[(3-tert-Butylphenyl)sulfonyl]-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine(164.3 mg, 0.360 mmol, Example 113) in ethanol (5 mL) was added toRaney® nickel 2800 water slurry (202.9 mg, 1.556 mmol) in a 20 mLpressure bottle. The mixture was stirred under 30 psi of hydrogen atambient temperature for 15 hours. The mixture was filtered through apolypropylene membrane, the filtrate was concentrated, and the residuewas purified by column chromatography on silica gel eluted with ethylacetate/hexane (3:7) to give the title compound (56% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.20 (m, 6H), 1.33 (s, 9H), 1.62 (m, 1H), 1.94 (m,2H), 2.26 (m, 4H), 2.99 (m, 2H), 3.54 (m, 1H), 3.62 (m, 1H), 3.79 (m,1H), 5.20 (m, 1H), 7.59 (m, 2H), 7.67 (m, 1H), 7.78 (s, 1H), 8.06 (m,1H), 8.20 (m, 1H); MS (ESI) m/z 459 (M+H)⁺.

Example 118(7R,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

(7R,8aS)-7-{[5-(Prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine(196 mg, 0.418 mmol, Example 115) in ethanol (10 mL) was added to 20%palladium hydroxide on carbon (12 mg, 0.084 mmol). The mixture wasstirred at room temperature for 16 hours under 30 psi of hydrogen. Themixture was filtered through a nylon membrane and concentrated. Theresidue was purified by chromatography on silica gel (hexane/ethylacetate=1:1) to give the title compound (170 mg, 86%) as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.21 (s, 6H), 1.77 (m, 1H), 1.91 (m, 1H), 2.09(m, 1H), 2.20-2.30 (m, 2H), 2.39 (m, 2H), 3.01 (m, 2H), 3.56 (m, 1H),3.66 (m, 1H), 3.84 (m, 1H), 5.21 (m, 1H), 7.95 (m, 2H), 8.10 (m, 2H),8.26 (m, 1H), 8.38 (m, 1H); MS (ESI) m/z 471 (M+H)⁺.

Example 119(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4,5-trifluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3,4,5-trifluorobenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.06-8.12 (m, 2H) 7.71-7.77 (m, 2H) 5.41-5.48(m, 1H) 3.84 (dd, J=12.21, 6.10 Hz, 2H) 3.60-3.69 (m, 1H) 3.44-3.54 (m,1H) 3.34-3.42 (m, 1H) 3.01-3.17 (m, 3H) 2.87 (dd, J=12.97, 9.61 Hz, 1H)2.05-2.28 (m, 3H) 0.92-0.99 (m, 2H) 0.80-0.87 (m, 2H); MS (ESI) m/z 455(M+H)⁺.

Example 120(7R,8aS)-2-[(3-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-chloro-2-fluorobenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.06-8.11 (m, 2H) 7.89-7.95 (m, 1H) 7.77-7.82(m, 1H) 7.44-7.50 (m, 1H) 5.43-5.50 (m, 1H) 3.84-3.92 (m, 2H) 3.69 (d,J=13.12 Hz, 1H) 3.51 (d, 1H) 3.37-3.44 (m, 1H) 2.97-3.25 (m, 4H)2.06-2.31 (m, 3H) 0.93-0.99 (m, 2H) 0.81-0.87 (m, 2H); MS (ESI) m/z 453(M+H)⁺.

Example 121(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-fluoro-5-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-fluoro-5-methylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.06-8.12 (m, 2H) 7.54-7.63 (m, 2H) 7.34 (dd,J=10.53, 8.39 Hz, 1H) 5.42-5.51 (m, 1H) 3.81-3.94 (m, 2H) 3.51-3.71 (m,2H) 3.37-3.45 (m, 1H) 3.12-3.25 (m, 3H) 3.02 (dd, J=13.12, 9.46 Hz, 1H)2.38 (s, 3H) 2.07-2.32 (m, 3H) 0.93-1.00 (m, 2H) 0.80-0.86 (m, 2H); MS(ESI) m/z 433 (M+H)⁺.

Example 122(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,6-difluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,6-difluorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.06-8.12 (m, 2H) 7.72-7.83 (m, 1H) 7.30 (t, J=9.00 Hz, 2H) 5.44-5.51(m, 1H) 3.85-3.95 (m, 2H) 3.72 (d, J=13.12 Hz, 1H) 3.56 (s, 1H)3.39-3.46 (m, 1H) 3.04-3.26 (m, 4H) 2.07-2.34 (m, 3H) 0.91-1.01 (m, 2H)0.79-0.87 (m, 2H); MS (ESI) m/z 437 (M+H)⁺.

Example 123(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3,4-trifluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,3,4-trifluorobenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.11 (m, 2H) 7.64-7.74 (m, 1H) 7.45-7.54(m, 1H) 5.41-5.49 (m, 1H) 3.81-3.89 (m, 2H) 3.63-3.72 (m, 1H) 3.34-3.51(m, 2H) 2.93-3.21 (m, 4H) 2.06-2.28 (m, 3H) 0.92-0.99 (m, 2H) 0.81-0.86(m, 2H); MS (ESI) m/z 455 (M+H)⁺.

Example 124(7R,8aS)-2-[(5-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-fluoro-5-chlorobenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.12 (m, 2H) 7.76-7.84 (m, 2H) 7.49-7.56(m, 1H) 5.42-5.50 (m, 1H) 3.83-3.92 (m, 2H) 3.65-3.75 (m, 1H) 3.43-3.53(m, 1H) 3.35-3.41 (m, 1H) 2.96-3.24 (m, 4H) 2.06-2.31 (m, 3H) 0.92-0.99(m, 2H) 0.79-0.87 (m, 2H); MS (ESI) m/z 453 (M+H)⁺.

Example 125(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-fluoro-4-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-fluoro-4-methylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.08 (dd, J=11.60, 1.22 Hz, 2H) 7.48-7.63 (m,3H) 5.40-5.50 (m, 1H) 3.74-3.90 (m, 2H) 3.48-3.63 (m, J=13.12 Hz, 2H)3.35-3.44 (m, 1H) 3.09-3.22 (m, 2H) 2.93-3.05 (m, J=10.07 Hz, 1H) 2.83(dd, J=12.66, 9.92 Hz, 1H) 2.35 (d, J=1.83 Hz, 3H) 2.07-2.29 (m, 3H)0.92-0.99 (m, 2H) 0.80-0.86 (m, 2H); MS (ESI) m/z 433 (M+H)⁺.

Example 126(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-difluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3,5-difluorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.11 (m, 2H) 7.47-7.60 (m, 3H) 5.38-5.47 (m, 1H) 3.78-3.88 (m, 2H)3.61-3.68 (m, 1H) 3.32-3.48 (m, 2H) 2.96-3.13 (m, J=3.66 Hz, 3H)2.77-2.87 (m, 1H) 2.07-2.27 (m, 3H) 0.92-0.99 (m, 2H) 0.80-0.86 (m, 2H);MS (ESI) m/z 437 (M+H)⁺.

Example 127(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-dimethylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3,5-dimethylbenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.10(d, J=1.22 Hz, 1H) 8.07-8.08 (m, 1H) 7.36-7.41 (m, 3H) 5.41-5.51 (m, 1H)3.88 (dd, J=12.36, 6.26 Hz, 1H) 3.76 (dd, J=12.66, 2.90 Hz, 1H)3.50-3.65 (m, 2H) 3.35-3.46 (m, 1H) 3.12-3.25 (m, 2H) 2.99 (t, J=9.92Hz, 1H) 2.84 (dd, J=12.66, 9.31 Hz, 1H) 2.39 (s, 6H) 2.08-2.31 (m, 3H)0.92-0.99 (m, 2H) 0.81-0.86 (m, 2H); MS (ESI) m/z 429 (M+H)⁺.

Example 128(7R,8aS)-2-{[4-bromo-3-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyaolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-bromo-3-trifluoromethylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.18 (d, J=8.55 Hz, 1H) 7.95-8.10 (m, 4H)5.37-5.47 (m, 1H) 3.78-3.89 (m, 2H) 3.62-3.69 (m, 1H) 3.32-3.48 (m, 2H)2.94-3.13 (m, J=7.02 Hz, 3H) 2.75-2.91 (m, 1H) 2.06-2.27 (m, 3H)0.92-1.00 (m, 2H) 0.80-0.86 (m, 2H); MS (ESI) m/z 547 (M+H)⁺.

Example 129(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-fluoro-2-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-fluoro-2-methylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.09 (dd, J=11.14, 1.37 Hz, 2H) 7.92 (dd,J=8.85, 5.80 Hz, 1H) 7.18-7.34 (m, 2H) 5.43-5.51 (m, 1H) 3.92 (dd,J=12.51, 6.41 Hz, 1H) 3.79 (dd, J=13.12, 3.36 Hz, 1H) 3.52-3.65 (m, 2H)3.37-3.46 (m, 1H) 3.11-3.27 (m, 3H) 3.06 (dd, J=13.28, 9.61 Hz, 1H) 2.59(s, 3H) 2.04-2.35 (m, 3H) 0.93-1.00 (m, 2H) 0.81-0.86 (m, 2H); MS (ESI)m/z 433 (M+H)⁺.

Example 130(7R,8aS)-2-[(4-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-chloro-2-fluorobenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.12 (m, 2H) 7.84 (t, J=8.09 Hz, 1H) 7.67(dd, J=10.22, 1.98 Hz, 1H) 7.52 (dd, J=8.54, 1.83 Hz, 1H) 5.44-5.52 (m,1H) 3.82-3.94 (m, 2H) 3.56-3.71 (m, 2H) 3.39-3.51 (m, 1H) 3.16-3.27 (m,3H) 3.06 (dd, J=13.12, 9.46 Hz, 1H) 2.06-2.36 (m, 3H) 0.92-1.00 (m, 2H)0.81-0.88 (m, 2H); MS (ESI) m/z 453 (M+H)⁺.

Example 131(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-difluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,5-difluorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.06-8.13 (m, 2H) 7.49-7.65 (m, 3H) 5.42-5.55 (m, 1H) 3.85-3.96 (m, 2H)3.60-3.75 (m, 2H) 3.42-3.52 (m, 1H) 3.18-3.28 (m, 3H) 3.11 (dd, J=13.12,9.46 Hz, 1H) 2.07-2.35 (m, 3H) 0.93-1.01 (m, 2H) 0.81-0.87 (m, 2H); MS(ESI) m/z 437 (M+H)⁺.

Example 132(7R,8aS)-2-[(3-chloro-4-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-chloro-4-methylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.02-8.13 (m, 2H) 7.77 (d, J=1.53 Hz, 1H)7.58-7.70 (m, 2H) 5.35-5.52 (m, 1H) 3.70-3.91 (m, 2H) 3.41-3.65 (m,J=12.82 Hz, 2H) 3.35-3.43 (m, 1H) 3.05-3.19 (m, 2H) 2.93-3.04 (m, 1H)2.82 (dd, J=12.51, 9.46 Hz, 1H) 2.45 (s, 3H) 2.04-2.30 (m, 3H) 0.90-1.00(m, 2H) 0.79-0.87 (m, 2H); MS (ESI) m/z 449 (M+H)⁺.

Example 133(7R,8aS)-2-[(4-bromo-3-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-bromo-3-methylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.08 (dd, J=10.99, 1.53 Hz, 2H) 7.86 (d,J=8.24 Hz, 1H) 7.73 (d, J=2.14 Hz, 1H) 7.53 (dd, J=8.54, 2.14 Hz, 1H)5.40-5.47 (m, 1H) 3.73-3.89 (m, 2H) 3.59 (d, J=12.82 Hz, 1H) 3.40-3.51(m, 1H) 3.33-3.39 (m, 1H) 3.02-3.15 (m, 2H) 2.90-3.00 (m, 1H) 2.78 (dd,J=12.36, 9.61 Hz, 1H) 2.47 (s, 3H) 2.04-2.29 (m, 3H) 0.92-1.00 (m, 2H)0.80-0.86 (m, 2H); MS (ESI) m/z 493 (M+H)⁺.

Example 134(7R,8aS)-2-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyaolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-bromo-5-trifluoromethylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.23 (d, J=1.83 Hz, 1H) 8.14 (d, J=8.24 Hz,1H) 8.05-8.10 (m, 2H) 7.93 (dd, J=8.09, 1.98 Hz, 1H) 5.36-5.50 (m,J=6.71 Hz, 1H) 3.90-3.97 (m, 1H) 3.84 (dd, J=11.90, 6.41 Hz, 1H) 3.75(d, J=10.68 Hz, 1H) 3.28-3.37 (m, 3H) 2.85-3.13 (m, 3H) 2.04-2.23 (m,3H) 0.92-1.00 (m, 2H) 0.80-0.86 (m, 2H).

Example 135(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(mesitylsulfonyl)-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting mesitylsulfonylchloride for 4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz,DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.06-8.11 (m, 2H) 7.08 (s, 2H)5.43-5.50 (m, 1H) 3.90 (dd, J=12.21, 6.41 Hz, 1H) 3.68 (dd, J=13.12,3.05 Hz, 1H) 3.32-3.52 (m, 3H) 3.11-3.21 (m, 2H) 2.98-3.09 (m, 2H) 2.56(s, 6H) 2.29 (s, 3H) 2.05-2.24 (m, 3H) 0.91-0.99 (m, 2H) 0.78-0.87 (m,2H); MS (ESI) m/z 443 (M+H)⁺.

Example 136(7R,8aS)-2-(biphenyl-4-ylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substitutingbiphenyl-4-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride. ¹HNMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.05-8.10 (m, 2H)7.84-7.96 (m, 4H) 7.70-7.76 (m, 2H) 7.43-7.56 (m, 3H) 5.36-5.45 (m, 1H)3.81 (dd, J=11.90, 6.41 Hz, 2H) 3.58-3.67 (m, 1H) 3.31-3.42 (m, 2H)2.90-3.10 (m, 3H) 2.68-2.83 (m, 1H) 2.05-2.30 (m, 3H) 0.92-0.99 (m, 2H)0.79-0.87 (m, 2H); MS (ESI) m/z 477 (M+H)⁺.

Example 137(7R,8aS)-2-[(3-bromophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-bromobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.06-8.12 (m, 2H) 7.90-7.95 (m, 2H) 7.78-7.82 (m, 1H) 7.63 (t, J=8.09Hz, 1H) 5.36-5.49 (m, 1H) 3.78-3.87 (m, 2H) 3.62 (d, J=12.51 Hz, 1H)3.33-3.47 (m, 2H) 2.92-3.12 (m, 3H) 2.74-2.86 (m, 1H) 2.04-2.28 (m, 3H)0.92-0.99 (m, 2H) 0.80-0.86 (m, 2H); MS (ESI) m/z 479 (M+H)⁺.

Example 138(7R,8aS)-2-{[2,5-bis(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,5-bis(trifluoromethyl)benzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.27-8.32 (m, 3H) 8.06-8.12 (m, 2H) 5.44-5.50(m, 1H) 3.87-4.00 (m, 2H) 3.74 (d, J=13.73 Hz, 1H) 3.35-3.55 (m, 2H)3.05-3.22 (m, 4H) 2.07-2.33 (m, 3H) 0.92-1.00 (m, 2H) 0.80-0.87 (m, 2H);MS (ESI) m/z 537 (M+H)⁺.

Example 139(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-fluoro-2-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting5-fluoro-2-methylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.06-8.12 (m, 2H) 7.37-7.66 (m, 3H) 5.44-5.52(m, 1H) 3.92 (dd, J=12.51, 6.41 Hz, 1H) 3.83 (dd, J=13.12, 3.36 Hz, 1H)3.50-3.73 (m, 2H) 3.39-3.46 (m, 1H) 3.04-3.27 (m, 4H) 2.55 (s, 3H)2.07-2.31 (m, 3H) 0.92-0.99 (m, 2H) 0.80-0.87 (m, 2H); MS (ESI) m/z 433(M+H)⁺.

Example 140(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dichloro-3-thienyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,5-dichlorothiophene-3-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.06-8.11 (m, 2H) 7.31 (s, 1H) 5.43-5.50 (m, 1H) 3.84-3.92 (m, 2H)3.66-3.74 (m, 1H) 3.36-3.52 (m, 2H) 2.98-3.24 (m, 4H) 2.05-2.29 (m, 3H)0.93-0.98 (m, 2H) 0.81-0.88 (m, 2H); MS (ESI) m/z 475 (M+H)⁺.

Example 141(7R,8aS)-2-[(5-chloro-2-thienyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting5-chlorothiophene-2-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.12 (m, 2H) 7.57 (d, J=4.27 Hz, 1H) 7.31 (d, J=3.97 Hz, 1H)5.42-5.49 (m, 1H) 3.76-3.92 (m, 2H) 3.57-3.65 (m, 1H) 3.45-3.55 (m, 1H)3.37-3.44 (m, 1H) 2.99-3.17 (m, 3H) 2.87 (dd, J=12.66, 9.61 Hz, 1H)2.06-2.30 (m, 3H) 0.92-1.00 (m, 2H) 0.81-0.87 (m, 2H); MS (ESI) m/z 441(M+H)⁺.

Example 142(7R,8aS)-2-[(4-chlorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-chlorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.10 (m, 2H) 7.78-7.84 (m, 2H) 7.69-7.74 (m, 2H) 5.37-5.47 (m, 1H)3.75-3.86 (m, 2H) 3.59 (d, J=12.21 Hz, 1H) 3.30-3.45 (m, 2H) 2.89-3.10(m, 3H) 2.70-2.79 (m, 1H) 2.07-2.25 (m, 3H) 0.92-1.00 (m, 2H) 0.80-0.86(m, 2H); MS (ESI) m/z 435 (M+H)⁺.

Example 143(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-fluorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-fluorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.06-8.11 (m, 2H) 7.84-7.93 (m, 2H) 7.43-7.51 (m, 2H) 5.40-5.52 (m, 1H)3.87 (dd, J=12.51, 6.41 Hz, 1H) 3.78 (dd, J=12.97, 3.51 Hz, 1H) 3.58 (d,J=12.51 Hz, 2H) 3.37-3.45 (m, 1H) 3.12-3.25 (m, 2H) 3.02 (t, 1H) 2.85(dd, J=12.51, 9.46 Hz, 1H) 2.08-2.31 (m, 3H) 0.91-0.99 (m, 2H) 0.79-0.88(m, 2H); MS (ESI) m/z 419 (M+H)⁺.

Example 144(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-fluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-fluorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.06-8.11 (m, 2H) 7.71-7.80 (m, 1H) 7.63-7.69 (m, 1H) 7.54-7.63 (m, 2H)5.42-5.51 (m, 1H) 3.78-3.93 (m, 2H) 3.55-3.66 (m, 2H) 3.37-3.46 (m, 1H)3.13-3.26 (m, 2H) 3.00-3.10 (m, 1H) 2.90 (dd, J=13.12, 9.46 Hz, 1H)2.07-2.34 (m, 3H) 0.92-1.00 (m, 2H) 0.80-0.87 (m, 2H); MS (ESI) m/z 419(M+H)⁺.

Example 145(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-methylbenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.04-8.11 (m, 2H) 7.51-7.63 (m, 4H) 5.39-5.50 (m, 1H) 3.86 (dd, J=12.21,6.41 Hz, 1H) 3.77 (dd, J=12.82, 3.05 Hz, 1H) 3.46-3.63 (m, J=12.82 Hz,2H) 3.35-3.43 (m, 1H) 3.06-3.21 (m, 2H) 2.91-3.03 (m, 1H) 2.81 (dd,J=12.66, 9.61 Hz, 1H) 2.43 (s, 3H) 2.06-2.31 (m, 3H) 0.92-1.01 (m, 2H)0.79-0.85 (m, 2H); MS (ESI) m/z 415 (M+H)⁺.

Example 1462-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}benzonitrile

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-cyanobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.19 (m, 4H) 7.87-8.00 (m, 2H) 5.40-5.50 (m, 1H) 3.83-3.95 (m, 2H)3.72 (d, J=13.43 Hz, 1H) 3.47-3.58 (m, 1H) 3.38-3.47 (m, 1H) 2.99-3.27(m, 4H) 2.05-2.31 (m, 3H) 0.92-1.08 (m, 2H) 0.78-0.87 (m, 2H); MS (ESI)m/z 426 (M+H)⁺.

Example 147(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methoxyphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-methoxybenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) 8 ppm 8.09(d, J=11.29 Hz, 2H) 7.71-7.80 (m, 2H) 7.13-7.21 (m, 2H) 5.41-5.49 (m,1H) 3.83-3.91 (m, 4H) 3.68-3.78 (m, 1H) 3.47-3.64 (m, J=13.12 Hz, 2H)3.37-3.46 (m, 1H) 3.13-3.25 (m, 2H) 2.98 (t, J=9.77 Hz, 1H) 2.82 (dd,J=12.51, 9.46 Hz, 1H) 2.03-2.33 (m, 3H) 0.90-1.03 (m, 2H) 0.79-0.90 (m,2H); MS (ESI) m/z 431 (M+H)⁺.

Example 148(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-dichlorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3,5-dichlorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.12 (m, 2H) 7.93 (t, J=1.83 Hz, 1H) 7.78 (d, J=1.83 Hz, 2H)5.41-5.50 (m, 1H) 3.82-3.92 (m, 2H) 3.63-3.69 (m, 1H) 3.46-3.58 (m, 1H)3.36-3.44 (m, 1H) 3.01-3.22 (m, 3H) 2.90 (dd, J=12.82, 9.46 Hz, 1H)2.07-2.28 (m, 3H) 0.91-1.00 (m, 2H) 0.80-0.86 (m, 2H); MS (ESI) m/z 469(M+H)⁺.

Example 149(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3-dichlorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,3-dichlorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.12 (m, 2H) 8.01 (dd, J=8.09, 1.37 Hz, 1H) 7.90-7.96 (m, 1H) 7.59(t, J=8.09 Hz, 1H) 5.43-5.52 (m, 1H) 3.84-3.96 (m, 2H) 3.67-3.76 (m, 1H)3.44-3.54 (m, 1H) 3.30-3.42 (m, 2H) 3.05-3.23 (m, 3H) 2.05-2.30 (m, 3H)0.91-1.04 (m, 2H) 0.80-0.86 (m, 2H); MS (ESI) m/z 469 (M+H)⁺.

Example 150(7R,8aS)-2-[(4-bromophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-bromobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.10 (m, 2H) 7.83-7.89 (m, 2H) 7.70-7.76 (m, 2H) 5.36-5.44 (m, 1H)3.74-3.85 (m, 2H) 3.54-3.65 (m, 1H) 3.28-3.38 (m, 2H) 2.83-3.13 (m, 3H)2.65-2.77 (m, 1H) 2.05-2.24 (m, 3H) 0.91-0.99 (m, 2H) 0.80-0.87 (m, 2H);MS (ESI) m/z 479 (M+H)⁺.

Example 151(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4-dichlorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3,4-dichlorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.12 (m, 2H) 7.97 (d, J=2.14 Hz, 1H) 7.90 (d, J=8.54 Hz, 1H) 7.77(dd, J=8.54, 2.14 Hz, 1H) 5.37-5.46 (m, 1H) 3.77-3.88 (m, 2H) 3.58-3.66(m, 1H) 3.32-3.48 (m, 2H) 2.91-3.14 (m, 3H) 2.81 (dd, J=12.36, 9.92 Hz,1H) 2.05-2.27 (m, 3H) 0.91-0.99 (m, 2H) 0.79-0.87 (m, 2H); MS (ESI) m/z469 (M+H)⁺.

Example 152(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dichlorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,5-dichlorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.07-8.12 (m, 2H) 7.98 (d, J=2.44 Hz, 1H) 7.71-7.77 (m, 2H) 5.45-5.53(m, 1H) 3.88-3.98 (m, J=12.36, 6.26 Hz, 2H) 3.70-3.78 (m, 1H) 3.54-3.65(m, 1H) 3.33-3.47 (m, 2H) 3.14-3.27 (m, 3H) 2.08-2.34 (m, 3H) 0.93-1.03(m, 2H) 0.81-0.88 (m, 2H); MS (ESI) m/z 469 (M+H)⁺.

Example 1534-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}benzonitrile

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-cyanobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.10(d, J=1.83 Hz, 2H) 8.06-8.09 (m, 2H) 7.98 (d, J=8.54 Hz, 2H) 5.41-5.47(m, 1H) 3.78-3.90 (m, 2H) 3.63 (d, J=12.51 Hz, 1H) 3.45-3.56 (m, 1H)3.34-3.41 (m, 1H) 2.97-3.19 (m, 3H) 2.86 (dd, J=12.97, 9.61 Hz, 1H)2.03-2.32 (m, 3H) 0.90-1.02 (m, 2H) 0.77-0.88 (m, 2H); MS (ESI) m/z 426(M+H)⁺.

Example 154(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,4-dichlorophenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,4-dichlorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.07-8.11 (m, 2H) 8.01 (d, J=8.54 Hz, 1H) 7.83 (d, J=2.14 Hz, 1H) 7.64(dd, J=8.54, 2.14 Hz, 1H) 5.44-5.51 (m, 1H) 3.90 (dd, J=12.21, 6.10 Hz,2H) 3.65-3.75 (m, 1H) 3.45-3.59 (m, 1H) 3.37-3.44 (m, 1H) 3.31-3.35 (m,J=3.05 Hz, 1H) 3.06-3.24 (m, 3H) 2.06-2.31 (m, 3H) 0.92-1.01 (m, 2H)0.80-0.86 (m, 2H); MS (ESI) m/z 469 (M+H)⁺.

Example 155(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(1-naphthylsulfonyl)-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substitutingnaphthalene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride.¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) 8 ppm 8.61 (d, J=8.54Hz, 1H) 8.29 (d, J=8.24 Hz, 1H) 8.17-8.22 (m, 1H) 8.11 (d, J=7.32 Hz,1H) 8.02-8.09 (m, 2H) 7.65-7.79 (m, 3H) 5.37-5.48 (m, 1H) 3.80-3.93 (m,2H) 3.64-3.72 (m, 1H) 3.40-3.53 (m, 1H) 3.33-3.40 (m, 1H) 2.95-3.23 (m,4H) 2.06-2.26 (m, 3H) 0.92-0.99 (m, 2H) 0.80-0.86 (m, 2H); MS (ESI) m/z451 (M+H)⁺.

Example 156(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-naphthylsulfonyl)-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substitutingnaphthalene-2-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride.¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.46 (d, J=1.83Hz, 1H) 8.14-8.21 (m, 2H) 8.03-8.11 (m, 3H) 7.67-7.89 (m, 3H) 5.36-5.51(m, 1H) 3.77-3.91 (m, 2H) 3.53-3.73 (m, 2H) 3.35-3.47 (m, 1H) 3.12-3.23(m, 2H) 3.00-3.10 (m, 1H) 2.90 (dd, J=12.66, 9.31 Hz, 1H) 2.05-2.34 (m,3H) 0.91-1.01 (m, 2H) 0.79-0.86 (m, 2H); MS (ESI) m/z 451 (M+H)⁺.

Example 157(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-propylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-propylbenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.04-8.12 (m, 2H) 7.71 (d, J=8.54 Hz, 2H) 7.48 (d, J=8.24 Hz, 2H)5.39-5.49 (m, 1H) 3.87 (dd, J=12.51, 6.41 Hz, 1H) 3.76 (dd, J=12.97,3.20 Hz, 1H) 3.50-3.64 (m, J=12.82 Hz, 2H) 3.36-3.45 (m, 1H) 3.10-3.25(m, 2H) 2.92-3.04 (m, J=10.07 Hz, 1H) 2.84 (dd, J=12.51, 9.46 Hz, 1H)2.68 (t, J=7.48 Hz, 2H) 1.98-2.33 (m, 3H) 1.57-1.73 (m, 2H) 0.88-1.01(m, 5H) 0.79-0.87 (m, 2H); MS (ESI) m/z 443 (M+H)⁺.

Example 158(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-methylbenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.13 (m, 2H) 7.64-7.88 (m, 1H) 7.57-7.65 (m, J=7.48, 7.48 Hz, 1H)7.42-7.50 (m, 2H) 5.41-5.55 (m, 1H) 3.87-3.97 (m, 1H) 3.74-3.83 (m,J=13.73, 3.36 Hz, 1H) 3.52-3.68 (m, 2H) 3.38-3.50 (m, 1H) 3.14-3.26 (m,2H) 3.02-3.13 (m, J=13.12, 9.46 Hz, 2H) 2.58 (s, 3H) 2.04-2.33 (m, 3H)0.91-0.97 (m, 2H) 0.77-0.86 (m, 2H); MS (ESI) m/z 415 (M+H)⁺.

Example 1593-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}benzonitrile

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-cyanobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.17-8.23 (m, 1H) 8.09-8.17 (m, 2H) 8.06-8.09 (m, J=10.53, 1.37 Hz, 2H)7.87 (t, J=7.93 Hz, 1H) 5.37-5.45 (m, 1H) 3.76-3.88 (m, 2H) 3.57-3.69(m, J=7.93 Hz, 1H) 3.30-3.45 (m, 1H) 2.94-3.10 (m, 4H) 2.79 (t, 1H)2.05-2.27 (m, 3H) 0.90-0.99 (m, 2H) 0.81-0.85 (m, 2H); MS (ESI) m/z 426(M+H)⁺.

Example 160(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dimethoxyphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,5-dimethoxybenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.07-8.12 (m, 2H) 7.19-7.32 (m, 3H) 5.44-5.55 (m, 1H) 3.88-3.97 (m, 1H)3.87 (s, 3H) 3.80-3.86 (m, 1H) 3.78 (s, 3H) 3.58-3.70 (m, 2H) 3.39-3.46(m, 1H) 3.33-3.36 (m, J=2.44 Hz, 1H) 3.16-3.26 (m, 2H) 3.12 (dd,J=13.73, 9.16 Hz, 1H) 2.05-2.37 (m, 3H) 0.92-1.01 (m, 2H) 0.81-0.86 (m,2H); MS (ESI) m/z 461 (M+H)⁺.

Example 161(7R,8aS)-2-[(3-chloro-4-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-chloro-4-fluorobenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.08 (dd, J=11.29, 1.53 Hz, 2H) 7.98 (dd,J=6.71, 2.14 Hz, 1H) 7.81-7.87 (m, 1H) 7.65 (t, J=8.85 Hz, 1H) 5.37-5.51(m, 1H) 3.77-3.90 (m, 2H) 3.63 (d, J=12.82 Hz, 1H) 3.46-3.58 (m, 1H)3.35-3.43 (m, 1H) 2.97-3.21 (m, 3H) 2.86 (dd, J=12.82, 9.77 Hz, 1H)1.98-2.34 (m, 3H) 0.91-1.00 (m, 2H) 0.78-0.87 (m, 2H); MS (ESI) m/z 453(M+H)⁺.

Example 162(7R,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

(7R,8aS)-7-{[5-(Prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine(240 mg, 0.512 mmol, Example 116) in ethanol (10 mL) was added to 20%palladium hydroxide on carbon (15 mg, 0.11 mmol). The mixture wasstirred at room temperature for 16 hours under 30 psi of hydrogen. Themixture was filtered through a nylon membrane and concentrated. Theresidue was purified by chromatography on silica gel (hexane/ethylacetate=3:2) to give the title compound (217 mg, 90% yield) as a solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (s, 6H), 1.77 (m, 1H), 1.91 (m,1H), 2.09 (m, 1H), 2.21-2.42 (m, 4H), 3.01 (m, 2H), 3.56 (m, 1H), 3.66(m, 1H), 3.84 (m, 1H), 5.22 (m, 1H), 8.02 (m, 5H), 8.20 (m, 1H); MS(ESI) m/z 471 (M+H)⁺.

Example 1635-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-1-methyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting1-methyl-2-oxoindoline-5-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃) δ ppm0.89-1.07 (m, 4H) 1.91-2.08 (m, 2H) 2.40 (dd, J=13.49, 5.55 Hz, 4H)2.77-3.20 (m, 4H) 3.27 (s, 3H) 3.62 (s, 2H) 5.44-5.61 (m, J=3.17 Hz, 1H)6.95 (d, J=8.33 Hz, 1H) 7.61 (s, 1H) 7.73 (dd, J=8.33, 1.59 Hz, 1H) 7.93(d, J=1.59 Hz, 1H) 8.09 (d, J=1.19 Hz, 1H); MS (ESI) m/z 470 (M+H)⁺.

Example 164(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-ethyl-2-thienyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting5-ethylthiophene-2-sulfonyl chloride for 6-morpholinopyridine-3-sulfonylchloride. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.90-1.03 (m, 4H) 1.35 (t,J=7.54 Hz, 3H) 1.92-2.07 (m, 2H) 2.28-2.41 (m, 2H) 2.40-2.57 (m, 1H)2.90 (q, J=7.54 Hz, 2H) 2.96-3.27 (m, 3H) 3.39-3.73 (m, J=21.42 Hz, 2H)3.88-4.43 (m, 2H) 5.44-5.62 (m, 1H) 6.83-6.89 (m, J=3.57 Hz, 1H) 7.41(d, J=3.97 Hz, 1H) 7.93 (d, J=1.59 Hz, 1H) 8.08 (d, J=1.19 Hz, 1H); MS(ESI) m/z 435 (M+H)⁺.

Example 165(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(1-ethyl-1H-pyrazol-4-yl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting1-ethyl-1H-pyrazole-4-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃) δ ppm0.87-1.07 (m, 4H) 1.54 (t, J=7.34 Hz, 3H) 1.93-2.07 (m, 2H) 2.34-2.43(m, 2H) 2.43-2.64 (m, 2H) 2.74-3.34 (m, 4H) 3.43-3.77 (m, 2H) 4.24 (q,J=7.14 Hz, 2H) 5.46-5.62 (m, 1H) 7.76 (s, 1H) 7.80 (s, 1H) 7.93 (d,J=1.19 Hz, 1H) 8.08 (d, J=1.59 Hz, 1H); MS (ESI) m/z 419 (M+H)⁺.

Example 166(7R,8aS)-7-[(2-cyclopropylpyrimidin-4-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The procedures for Examples 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting4-chloro-2-cyclopropylpyrimidine for 2-bromo-5-cyclopropylpyrazine togive the title compound (26% yield) as a solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.99 (m, 3H), 1.90 (m, 2H), 2.07 (m, 3H), 2.27 (m, 3H),2.97 (m, 1H), 3.52 (m, 1H), 3.64 (m, 1H), 3.85 (m, 1H), 5.21 (m, 1H),6.64 (m, 1H), 7.95 (m, 2H), 8.12 (s, 2H), 8.31 (m, 2H); MS (ESI) m/z 469(M+H)⁺.

Example 167(7R,8aS)-7-[(2-cyclopropylpyrimidin-4-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The procedures for Examples 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol, substituting4-chloro-2-cyclopropylpyrimidine for 2-bromo-5-cyclopropylpyrazine, andsubstituting 4-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (26% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99(m, 3H), 1.90 (m, 2H), 2.07 (m, 3H), 2.27 (m, 3H), 2.97 (m, 1H), 3.52(m, 1H), 3.64 (m, 1H), 3.85 (m, 1H), 5.21 (m, 1H), 6.64 (m, 1H), 7.98(m, 2H), 8.04 (s, 2H), 8.31 (m, 2H); MS (ESI) m/z 469 (M+H)⁺.

Example 168(7R,8aS)-2-[(5-tert-butyl-2-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting5-tert-butyl-2-methylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.12 (m, 2H) 7.77-7.82 (m, 1H) 7.61 (dd,J=7.93, 2.14 Hz, 1H) 7.39 (d, J=8.24 Hz, 1H) 5.40-5.49 (m, 1H) 3.87 (dd,J=11.90, 6.41 Hz, 1H) 3.78 (dd, J=13.12, 3.05 Hz, 1H) 3.57 (d, J=12.51Hz, 1H) 3.31-3.44 (m, 2H) 2.85-3.17 (m, 4H) 2.54 (s, 3H) 2.05-2.30 (m,3H) 1.31 (s, 9H) 0.90-1.00 (m, 2H) 0.79-0.88 (m, 2H); MS (ESI) m/z 471(M+H)⁺.

Example 169(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.04-8.11 (m, 2H) 7.45-7.51 (m, 2H) 7.29-7.37(m, 1H) 5.43 (dd, J=4.12, 1.98 Hz, 1H) 3.84 (dd, J=12.21, 6.41 Hz, 1H)3.71-3.78 (m, 1H) 3.41-3.61 (m, J=12.51 Hz, 2H) 3.33-3.40 (m, 1H)3.02-3.16 (m, 2H) 2.92 (t, 1H) 2.66-2.86 (m, 5H) 2.04-2.29 (m, 3H)1.71-1.84 (m, 4H) 0.91-1.03 (m, 2H) 0.81-0.86 (m, 2H); MS (ESI) m/z 455(M+H)⁺.

Example 170(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methoxy-3-methylphenyl)sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-methoxy-3-methylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.11 (m, 2H) 7.63 (dd, J=8.70, 2.29 Hz,1H) 7.56 (d, J=1.53 Hz, 1H) 7.17 (d, J=8.54 Hz, 1H) 5.41-5.50 (m, 1H)3.83-3.93 (m, 4H) 3.73 (dd, J=12.66, 2.90 Hz, 1H) 3.48-3.64 (m, J=13.12Hz, 2H) 3.36-3.45 (m, 1H) 3.12-3.24 (m, 2H) 2.95 (t, J=9.92 Hz, 1H) 2.80(dd, J=12.51, 9.77 Hz, 1H) 2.16-2.36 (m, 5H) 2.07-2.16 (m, 1H) 0.92-1.02(m, 2H) 0.80-0.87 (m, 2H); MS (ESI) m/z 445 (M+H)⁺.

Example 171(7R,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyaolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-chloro-3-trifluoromethylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.13 (m, 4H) 7.98-8.03 (m, 1H) 5.39-5.49(m, 1H) 3.81-3.90 (m, J=12.21, 6.41 Hz, 2H) 3.61-3.71 (m, 1H) 3.49-3.60(m, 1H) 3.37-3.45 (m, 1H) 3.02-3.22 (m, 3H) 2.90 (dd, J=12.82, 9.77 Hz,1H) 2.04-2.32 (m, 3H) 0.90-1.01 (m, 2H) 0.80-0.88 (m, 2H); MS (ESI) m/z503 (M+H)⁺.

Example 172(7R,8aS)-2-{[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyaolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-chloro-5-trifluoromethylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.22 (d, J=1.83 Hz, 1H) 8.01-8.11 (m, 3H)7.94-7.98 (m, 1H) 5.42-5.50 (m, 1H) 3.84-3.98 (m, 2H) 3.68-3.80 (m, 1H)3.31-3.46 (m, 2H) 3.00-3.21 (m, 4H) 2.05-2.31 (m, 3H) 0.92-1.00 (m, 2H)0.78-0.88 (m, 2H); MS (ESI) m/z 503 (M+H)⁺.

Example 173(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-methoxy-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-methoxy-5-trifluoromethylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.06-8.12 (m, 2H) 7.97-8.03 (m, 2H) 7.49 (d,J=9.46 Hz, 1H) 5.42-5.51 (m, 1H) 4.03 (s, 3H) 3.88 (dd, J=12.36, 6.26Hz, 2H) 3.62-3.74 (m, 1H) 3.44-3.60 (m, 1H) 3.33-3.44 (m, 1H) 3.16-3.25(m, 2H) 3.04-3.15 (m, 2H) 2.07-2.30 (m, 3H) 0.93-1.00 (m, 2H) 0.80-0.86(m, 2H); MS (ESI) m/z 499 (M+H)⁺.

Example 174(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2,3-dihydro-1H-inden-5-yl-sulfonyl)octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2,3-dihydro-1H-indene-5-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.06-8.14 (m, 2H) 7.62 (s, 1H) 7.52-7.60 (m, 1H) 7.46-7.52 (m, 1H)5.41-5.49 (m, 1H) 3.88 (dd, J=12.51, 6.41 Hz, 1H) 3.75 (dd, J=12.66,3.20 Hz, 1H) 3.49-3.66 (m, J=13.12 Hz, 2H) 3.37-3.46 (m, 1H) 3.14-3.25(m, 2H) 2.91-3.04 (m, 5H) 2.84 (dd, J=12.66, 9.00 Hz, 1H) 2.15-2.35 (m,2H) 2.04-2.15 (m, 3H) 0.92-1.01 (m, 2H) 0.79-0.87 (m, 2H); MS (ESI) m/z441 (M+H)⁺.

Example 175(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4-dimethylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3,4-dimethylbenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm8.05-8.12 (m, 2H) 7.48-7.58 (m, 2H) 7.39-7.45 (m, 1H) 5.40-5.50 (m, 1H)3.88 (dd, J=12.51, 6.41 Hz, 1H) 3.75 (dd, J=12.97, 3.20 Hz, 1H)3.49-3.65 (m, J=13.73 Hz, 2H) 3.37-3.46 (m, 1H) 3.11-3.26 (m, 2H) 2.99(t, J=10.68 Hz, 1H) 2.83 (dd, J=12.36, 9.31 Hz, 1H) 2.34 (s, 6H)2.05-2.30 (m, 3H) 0.92-0.98 (m, 2H) 0.78-0.88 (m, 2H); MS (ESI) m/z 429(M+H)⁺.

Example 176(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(1-methyl-1H-pyrazol-5-yl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-(1-methyl-1H-pyrazol-5-yl)benzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.12 (m, 2H) 7.77-7.91 (m, 4H) 7.51 (d,J=1.83 Hz, 1H) 6.50 (d, J=2.44 Hz, 1H) 5.43-5.51 (m, 1H) 3.80-3.95 (m,5H) 3.60-3.71 (m, 2H) 3.41-3.52 (m, 1H) 3.17-3.29 (m, 2H) 3.10 (t, 1H)2.95 (dd, J=12.97, 9.31 Hz, 1H) 2.17-2.38 (m, 2H) 2.06-2.16 (m, 1H)0.91-1.04 (m, 2H) 0.81-0.87 (m, 2H); MS (ESI) m/z 481 (M+H)⁺.

Example 177(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-methyl-6-(trifluoromethyl)pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.47 (d, J=8.24 Hz, 1H) 8.06-8.11 (m, 2H) 7.94(d, J=8.24 Hz, 1H) 5.43-5.51 (m, 1H) 3.83-3.95 (m, 2H) 3.65-3.77 (m, 1H)3.48-3.61 (m, 1H) 3.38-3.47 (m, 1H) 3.05-3.27 (m, 4H) 2.84 (s, 3H)2.06-2.30 (m, 3H) 0.91-1.01 (m, 2H) 0.81-0.87 (m, 2H); MS (ESI) m/z 484(M+H)⁺.

Example 178(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting2-morpholino-5-(trifluoromethyl)-benzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.10 (m, J=8.24, 1.53 Hz, 3H) 8.01 (dd,J=8.85, 2.14 Hz, 1H) 7.71 (d, J=8.54 Hz, 1H) 5.36-5.43 (m, J=7.02 Hz,1H) 3.85-3.93 (m, 1H) 3.74-3.82 (m, 5H) 3.64-3.72 (m, 1H) 3.09-3.22 (m,1H) 3.03-3.11 (m, 5H) 2.65-3.04 (m, 4H) 1.97-2.22 (m, 3H) 0.91-1.00 (m,2H) 0.77-0.86 (m, 2H); MS (ESI) m/z 554 (M+H)⁺.

Example 179(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(methoxymethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3-methoxymethylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.05-8.11 (m, 2H) 7.70-7.77 (m, 2H) 7.62-7.69(m, 2H) 5.39-5.50 (m, 1H) 4.54 (s, 2H) 3.86 (dd, J=12.21, 6.41 Hz, 1H)3.78 (dd, J=12.97, 3.20 Hz, 1H) 3.49-3.63 (m, 2H) 3.34-3.45 (m, 4H)3.11-3.23 (m, 2H) 2.99 (t, 1H) 2.79-2.88 (m, 1H) 2.04-2.32 (m, 3H)0.92-1.00 (m, 2H) 0.80-0.87 (m, 2H); MS (ESI) m/z 445 (M+H)⁺.

Example 180(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-methyl-3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-methyl-3-trifluoromethylbenzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.03-8.12 (m, 2H) 7.92-8.00 (m, 2H) 7.75 (d,J=7.93 Hz, 1H) 5.38-5.51 (m, 1H) 3.70-3.93 (m, 2H) 3.62 (d, J=12.51 Hz,1H) 3.42-3.51 (m, 1H) 3.33-3.41 (m, 1H) 2.91-3.18 (m, 3H) 2.81 (dd,J=12.51, 9.77 Hz, 1H) 2.57 (d, J=1.53 Hz, 3H) 2.05-2.29 (m, 3H)0.91-0.99 (m, 2H) 0.79-0.87 (m, 2H); MS (ESI) m/z 483 (M+H)⁺.

Example 1815-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-2-fluorobenzonitrile

The title compound was prepared using the procedure described in Example27C substituting 3-cyano-4-fluorobenzene-1-sulfonyl chloride for2-(trifluoromethyl)-benzene-1-sulfonyl chloride. ¹H NMR (300 MHz,DMSO-d₆) 8 ppm 0.74-0.87 (m, 2H), 0.87-0.99 (m, 2H), 1.68-1.96 (m, 2H),2.03-2.46 (m, 6H), 2.97 (d, J=10.9 Hz, 1H), 3.50-3.70 (m, 2H), 3.79 (d,J=10.2 Hz, 1H), 5.10-5.35 (m, 1H), 7.79 (t, J=9.0 Hz, 1H), 8.06-8.19 (m,3H), 8.37 (dd, J=6.1, 2.4 Hz, 1H); MS (ESI) m/z 444 (M+H)⁺.

Example 1822-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-4-methylbenzonitrile

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting2-cyano-5-methylbenzene-1-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃) δ ppm0.91-1.05 (m, 4H) 1.94-2.07 (m, 1H) 2.32-2.50 (m, 2H) 2.53 (s, 3H)2.85-3.24 (m, 3H) 3.29-3.78 (m, 4H) 3.78-4.48 (m, 2H) 5.42-5.63 (m, 1H)7.54 (dd, J=7.93, 0.79 Hz, 1H) 7.80 (d, J=7.93 Hz, 1H) 7.85 (s, 1H) 7.93(d, J=1.19 Hz, 1H) 8.09 (d, J=1.19 Hz, 1H); MS (ESI) m/z 440 (M+H)⁺.

Example 183(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(1-isopropyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt using theprocedure described in Example 70, substituting1-isopropyl-3-methyl-1H-pyrazole-4-sulfonyl chloride for6-morpholinopyridine-3-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃) δ ppm0.88-1.05 (m, 4H) 1.51 (d, J=6.78 Hz, 6H) 1.93-2.07 (m, 1H) 2.32-2.38(m, 1H) 2.40 (s, 3H) 2.76-3.40 (m, J=32.89 Hz, 5H) 3.42-4.10 (m, 4H)4.14-4.35 (m, 1H) 4.35-4.54 (m, 1H) 5.42-5.64 (m, 1H) 7.74 (s, 1H) 7.93(d, J=1.36 Hz, 1H) 8.08 (d, J=1.36 Hz, 1H); MS (ESI) m/z 447 (M+H)⁺.

Example 184(7R,8aS)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol

The procedure for making Example 19 was used substituting4-fluoro-3-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (81% yield). MS (ESI) m/z 369 (M+H)⁺.

Example 185(7R,8aS)-2-{[3-fluoro-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol

The procedure for making Example 19 was used substituting3-fluoro-5-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (80% yield). MS (ESI) m/z 369 (M+H)⁺.

Example 186(7R,8aS)-2-{[2-fluoro-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol

The procedure for making Example 19 was used substituting2-fluoro-5-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (80%). MS (ESI) m/z 369 (M+H)⁺.

Example 187(7R,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol

The procedure for making Example 19 was used substituting4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (81°/0 yield). MS (ESI) m/z 386 (M+H)⁺.

Example 188(7R,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}-7-ethoxy-octahydropyrrolo[1,2-a]pyrazine

To(7R,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol(0.3 mmol, Example 187) in tetrahydrofuran (1 mL) at room temperaturewas added NaH (20 mg, 60% in mineral oil). After 15 minutes, iodoethane(0.39 mmol) was added. The mixture was stirred at 60° C. for 2 days. Themixture was partially purified by chromatography on silica gel(CH₂Cl₂/CH₃OH=10:1) to give the title compound as an impure solid (77mg). The product was purified by HPLC (Gilson®, Xbridge™ 30×100 mmcolumn, eluted with pH=10 aqueous ammonium bicarbonate-ammoniumhydroxide/methanol (70:30 to 0:100 gradient over 16 minutes), flow rate36 mL/minute, UV=220 nm) to give the title compound (20 mg, 16% yield)as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (m, 3H), 1.47 (m, 1H),1.73 (m, 1H), 2.00 (m, 1H), 2.08 (m, 1H), 2.19 (m, 1H), 2.39 (m, 6H),2.93 (m, 1H), 3.63 (m, 1H), 3.76 (m, 1H), 3.92 (m, 1H), 8.04 (m, 3H); MS(ESI) m/z 469 (M+H)⁺.

Example 189(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,3,3-trifluoropropyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The procedures for Example 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]-pyrazin-7-ol and substituting3,3,3-trifluoropropane-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (96% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82(m, 2H), 0.91 (m, 2H), 1.81 (m, 2H), 2.11 (m, 1H), 2.24 (m, 2H), 2.33(m, 2H), 2.69 (m, 4H), 2.98 (m, 2H), 3.56 (m, 2H), 3.63 (m, 1H), 5.27(m, 1H), 8.13 (s, 2H); MS (ESI) m/z 421 (M+H)⁺.

Example 190(7S,8aR)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]-pyrazin-7-ol

To (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (0.208 g, 1.463 mmol)and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.358 g, 1.463 mmol)in dichloromethane (3 mL) was added triethylamine (303 mg, 3 mmol). Themixture was stirred at room temperature overnight. The mixture wasconcentrated and the residue was purified by chromatography on silicagel (CH₂Cl₂/CH₃OH=10:1) to give the title compound (0.4 g, 78% yield).MS (ESI) m/z 421 (M+H)⁺.

Example 191(7R,8aS)-2-(butylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substitutingbutane-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride. ¹HNMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.08-8.15 (m, 2H)5.47-5.56 (m, 1H) 3.91-4.01 (m, 1H) 3.81 (dd, J=13.58, 3.20 Hz, 1H) 3.63(dd, J=9.92, 3.20 Hz, 2H) 3.39-3.48 (m, 1H) 3.30-3.37 (m, 2H) 3.07-3.25(m, 4H) 2.20-2.36 (m, 2H) 2.07-2.18 (m, 1H) 1.63-1.75 (m, 2H) 1.37-1.51(m, 2H) 0.87-1.03 (m, 5H) 0.80-0.87 (m, 2H); MS (ESI) m/z 381 (M+H)⁺.

Example 192(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-thienylsulfonyl)-octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substitutingthiophene-2-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride.¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.06-8.16 (m,2H) 8.03 (dd, J=4.88, 1.22 Hz, 1H) 7.70 (dd, J=3.81, 1.37 Hz, 1H)7.24-7.35 (m, 1H) 5.40-5.50 (m, 1H) 3.90 (dd, J=12.51, 6.41 Hz, 1H) 3.79(dd, J=12.82, 3.36 Hz, 1H) 3.53-3.69 (m, 2H) 3.41-3.49 (m, 1H) 3.17-3.28(m, 2H) 3.00-3.13 (m, 1H) 2.92 (dd, J=12.82, 9.16 Hz, 1H) 2.04-2.36 (m,3H) 0.91-1.04 (m, 2H) 0.78-0.90 (m, 2H); MS (ESI) m/z 407 (M+H)⁺.

Example 193(7R,8aS)-2-(benzylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substitutingphenylmethanesulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride.¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.08 (d, J=5.80Hz, 2H) 7.36-7.46 (m, 5H) 5.33-5.45 (m, 1H) 4.43 (s, 2H) 3.78 (dd,J=11.44, 6.26 Hz, 1H) 3.65-3.73 (m, 1H) 3.45-3.56 (m, 1H) 3.16-3.22 (m,1H) 2.99-3.14 (m, 2H) 2.77 (d, J=71.11 Hz, 3H) 1.96-2.18 (m, 3H)0.89-1.00 (m, 2H) 0.83 (dd, J=5.04, 2.59 Hz, 2H); MS (ESI) m/z 415(M+H)⁺.

Example 194(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(isopropylsulfonyl)octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substitutingpropane-2-sulfonyl chloride for 4-methylbenzene-1-sulfonyl chloride. ¹HNMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.04-8.15 (m, 2H)5.46-5.55 (m, 1H) 3.90-3.99 (m, 1H) 3.86 (d, 1H) 3.50-3.72 (m, 2H)3.32-3.47 (m, 3H) 3.10-3.25 (m, 3H) 2.19-2.36 (m, 2H) 2.07-2.17 (m, 1H)1.27 (d, J=6.71 Hz, 6H) 0.90-1.01 (m, 2H) 0.79-0.88 (m, 2H); MS (ESI)m/z 367 (M+H)⁺.

Example 195(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting6-(trifluoromethyl)pyridine-3-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 9.13 (d, J=2.14 Hz, 1H) 8.49 (dd, J=8.24, 2.14Hz, 1H) 8.16 (d, J=8.24 Hz, 1H) 8.08 (d, J=8.85 Hz, 2H) 5.38-5.48 (m,1H) 3.78-3.97 (m, 2H) 3.66-3.76 (m, 1H) 3.33-3.51 (m, 2H) 3.02-3.16 (m,J=8.85 Hz, 3H) 2.90 (dd, J=12.21, 10.07 Hz, 1H) 2.05-2.29 (m, 3H)0.91-1.00 (m, 2H) 0.78-0.88 (m, 2H); MS (ESI) m/z 470 (M+H)⁺.

Example 196(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methylpyridin-2-yl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting4-methylpyridine-2-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.59(d, J=4.88 Hz, 1H) 8.04-8.12 (m, 2H) 7.78 (s, 1H) 7.53 (d, J=4.88 Hz,1H) 5.39-5.51 (m, 1H) 3.81-3.95 (m, 2H) 3.70 (m, 1H) 3.43-3.60 (m, 1H)3.35-3.42 (m, 2H) 3.03-3.19 (m, 3H) 2.46 (s, 3H) 2.04-2.32 (m, 3H)0.91-1.00 (m, 2H) 0.80-0.87 (m, 2H); MS (ESI) m/z 416 (M+H)⁺.

Example 197(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(6-methoxypyridin-3-yl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting6-methoxypyridine-3-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, temperature=90° C.) δ ppm 8.59(d, J=2.44 Hz, 1H) 8.00-8.15 (m, 3H) 7.04 (d, J=8.85 Hz, 1H) 5.39-5.50(m, 1H) 3.99 (s, 3H) 3.74-3.89 (m, 2H) 3.49-3.64 (m, J=13.43 Hz, 2H)3.34-3.45 (m, 1H) 3.08-3.22 (m, 2H) 3.02 (t, J=12.51 Hz, 1H) 2.84 (dd,J=12.51, 9.77 Hz, 1H) 2.01-2.33 (m, 3H) 0.92-1.00 (m, 2H) 0.80-0.88 (m,2H); MS (ESI) m/z 432 (M+H)⁺.

Example 1983-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-N,N-dimethylbenzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110 substituting3-(dimethylcarbamoyl)benzene-1-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, 90°C.) δ ppm 8.04-8.11 (m, 2H) 7.84-7.90 (m, 1H) 7.72-7.78 (m, 3H)5.39-5.49 (m, 1H) 3.78-3.90 (m, J=12.21, 6.41 Hz, 2H) 3.56-3.65 (m, 1H)3.44-3.56 (m, 1H) 3.35-3.43 (m, 1H) 3.07-3.21 (m, 2H) 2.92-3.06 (m, 7H)2.85 (t, J=11.60 Hz, 1H) 2.06-2.31 (m, 3H) 0.92-0.99 (m, 2H) 0.80-0.87(m, 2H); (ESI) m/z 472 (M+H)⁺.

Example 199(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-fluoropyridin-3-yl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110 substituting5-fluoropyridine-3-sulfonyl chloride for 4-methylbenzene-1-sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O, 90° C.) δ ppm 0.79-0.87 (m, 2H)0.92-1.01 (m, 2H) 2.06-2.16 (m, 1H) 2.17-2.34 (m, 2H) 2.99 (dd, J=13.12,9.46 Hz, 1H) 3.09-3.29 (m, 3H) 3.39-3.48 (m, 1H) 3.58-3.74 (m, 2H)3.83-3.94 (m, 2H) 5.42-5.51 (m, 1H) 8.07 (d, J=1.53 Hz, 1H) 8.09-8.15(m, 2H) 8.85 (s, 1H) 8.89 (d, J=2.75 Hz, 1H); (ESI) m/z 420 (M+H)⁺.

Example 2005-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-3,3-dimethyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure described in Example 110, substituting3,3-dimethyl-2-oxoindoline-5-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O,temperature=90° C.) δ ppm 8.04-8.08 (m, 2H) 7.62-7.68 (m, 2H) 7.11 (d,J=7.93 Hz, 1H) 5.34-5.44 (m, J=6.41 Hz, 1H) 3.71-3.84 (m, J=11.90, 6.41Hz, 2H) 3.49-3.60 (m, 1H) 3.28-3.38 (m, 2H) 2.81-3.06 (m, 3H) 2.69 (t,J=1.83 Hz, 1H) 2.62-2.77 (m, J=1.83 Hz, 1H) 2.04-2.26 (m, 3H) 1.33 (d,J=1.53 Hz, 6H) 0.91-0.98 (m, 2H) 0.80-0.86 (m, 2H); MS (ESI) m/z 484(M+H)⁺.

Example 2012-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-4-(trifluoromethyl)benzonitrileExample 201A(7R,8aS)-2-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 57, substituting 2-bromo-5-(trifluoromethyl)benzene-1-sulfonylchloride for 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride.

Example 201B2-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}-4-(trifluoromethyl)benzonitrile

To a solution of Example 201A (105 mg, 0.192 mmol) inN,N-dimethylformamide (1 mL) was added copper(I) cyanide (52 mg, 0.58mmol), and the resulting mixture was heated at 120° C. and stirred for24 hours. The cooled mixture was partitioned between water and ethylacetate, and the organic layer was dried over Na₂SO₄. The drying agentwas removed by filtration, the filtrate was concentrated in vacuo, andthe residue was purified on silica gel using a solvent gradient of 0-60%ethyl acetate in hexanes. The title compound was obtained as a colorlesssolid (70 mg, 74%). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.88-0.99 (m, 4H),1.77-1.91 (m, 1H), 1.93-2.06 (m, 2H), 2.35 (dd, J=10.00, 5.26 Hz, 1H),2.39-2.61 (m, 3H), 2.81-2.96 (m, 1H), 3.03 (dd, J=8.82, 2.37 Hz, 1H),3.68 (dd, J=10.17, 6.78 Hz, 1H), 3.89 (dd, J=10.51, 1.70 Hz, 1H),3.96-4.08 (m, 1H), 5.23-5.39 (m, 1H), 7.90-7.98 (m, 2H), 7.99-8.06 (m,2H), 8.30 (s, 1H); MS (ESI) m/z 494 (M+H)⁺.

Example 202(7R,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-{[5-(prop-1-en-2-yl)-pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazineExample 202A tert-butyl(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.0 g,7.03 mmol) in anhydrous dichloromethane (35 mL) was addeddi-tert-butyl-dicarbonate (1.714 mL, 7.38 mmol), and the resultingmixture was stirred at room temperature for 16 hours. The mixture waswashed with 1 N NaOH (20 mL) and water, and the organic extract wasdried over Na₂SO₄. The drying agent was removed by filtration, and thecrude product was purified by column chromatography on silica gel usinga solvent gradient of 0-10% methanol in dichloromethane. The titlecompound was obtained as a colorless oil (0.88 g, 52%).

Example 202B tert-butyl(7R,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of the product from Example 202A (0.88 g, 3.63 mmol)) inanhydrous tetrahydrofuran (20 mL) was added a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (4.36 mL, 4.36 mmol). Theresulting mixture was stirred at room temperature for 20 minutes, andthen 2-bromo-5-(prop-1-en-2-yl)pyrazine (0.867 g, 4.36 mmol) was added.The resulting dark mixture was stirred at room temperature for 16 hours,and the mixture was then poured into water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were dried overNa₂SO₄. The drying agent was removed by filtration, and the crudeproduct was purified by column chromatography on silica gel using asolvent gradient of 0-60% ethyl acetate in hexanes. The title compoundwas obtained as a light tan oil that crystallized on standing (0.67 g,51.2%).

Example 202C(7R,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]-pyrazinehydrochloride

To a solution of the product from Example 202B (100 mg, 0.277 mmol) in1,4-dioxane (1 mL) was added 4 N HCl in 1,4-dioxane (1 mL, 4.00 mmol).The resulting mixture was stirred at ambient temperature for 3 hours,and the mixture was then concentrated to give the title compound as anoff-white solid (82 mg, quantitative).

Example 202D(7R,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-{[5-(prop-1-en-2-yl)-pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 57, substituting the product from Example 202C (82 mg, 0.28mmol) for the product from Example 27B, and substituting the productfrom Example 58B for 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride.The title compound was obtained as a colorless solid (79 mg, 62%). ¹HNMR (300 MHz, CDCl₃) δ ppm 1.39 (s, 9H), 1.78-2.06 (m, 2H), 2.17 (s,3H), 2.31-2.49 (m, 2H), 2.50-2.62 (m, 1H), 2.61-2.74 (m, 1H), 2.91-3.06(m, 2H), 3.69 (dd, J=9.92, 6.74 Hz, 1H), 3.85-3.96 (m, 1H), 4.02-4.13(m, 1H), 5.22 (t, J=1.59 Hz, 1H), 5.32-5.42 (m, 1H), 5.77-5.81 (m,J=1.59 Hz, 1H), 7.51 (dd, J=7.54, 1.19 Hz, 1H), 7.71-7.84 (m, 2H), 8.15(d, J=1.59 Hz, 1H), 8.20 (d, J=1.19 Hz, 1H).

Example 203(7R,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-[(5-isopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine

To a solution of the product from Example 202D (21 mg, 0.046 mmol) intetrahydrofuran (10 mL) in a 50 mL pressure bottle was added 5%palladium on carbon, wet (4.20 mg, 0.039 mmol). The resulting mixturewas placed under H₂ gas (30 psi) and stirred for 15 minutes at roomtemperature. The mixture was filtered and concentrated in vacuo, and thecrude product was purified by column chromatography on silica gel usinga solvent gradient of 0-60% ethyl acetate in hexanes to give the titlecompound (18 mg, 85%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.29 (d, J=6.78 Hz,6H), 1.39 (s, 9H), 1.76-1.91 (m, 1H), 1.92-2.03 (m, 1H), 2.30-2.61 (m,3H), 2.67 (t, J=10.68 Hz, 1H), 2.92-3.08 (m, 3H), 3.68 (dd, J=9.83, 6.78Hz, 1H), 3.85-3.96 (m, 1H), 4.02-4.12 (m, 1H), 5.26-5.40 (m, 1H), 7.51(dd, J=7.80, 1.02 Hz, 1H), 7.71-7.84 (m, 2H), 7.91 (d, J=1.36 Hz, 1H),8.13 (d, J=1.36 Hz, 1H); MS (ESI) m/z 460 (M+H)⁺.

Example 204(7R,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[6-(trifluoromethyl)-pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

A solution of the product from Example 202B (100 mg, 0.277 mmol) inCH₂Cl₂ (2 mL) was treated dropwise with trifluoroacetic acid (1 mL,12.98 mmol), and the resulting mixture was stirred at room temperaturefor 30 minutes. The mixture was concentrated with a stream of dry N₂,and the residue was dried in vacuo. To this residue was added CH₂Cl₂(2.5 mL), (6-(trifluoromethyl)pyridine-2-sulfonyl chloride (102 mg,0.416 mmol)), and diisopropylethylamine (0.242 mL, 1.385 mmol), and theresulting mixture was stirred at room temperature for 3 hours. Themixture was partitioned between water and CH₂Cl₂, and the organic layerwas dried over Na₂SO₄. The drying agent was removed by filtration, andthe solution was concentrated in vacuo. The crude product was purifiedby column chromatography on silica gel using a solvent gradient of 0-40%ethyl acetate in hexanes. The title compound was obtained as a colorlesssolid (102 mg, 78%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.79-1.94 (m, 1H),1.94-2.06 (m, 1H), 2.18 (s, 3H), 2.37 (dd, J=9.83, 5.09 Hz, 1H),2.40-2.64 (m, 2H), 2.72 (t, J=10.85 Hz, 1H), 2.96-3.13 (m, 2H), 3.71(dd, J=9.83, 6.78 Hz, 1H), 3.93 (d, J=12.89 Hz, 1H), 4.08 (d, J=11.19Hz, 1H), 5.22 (t, J=1.53 Hz, 1H), 5.33-5.43 (m, 1H), 5.77-5.81 (m, 1H),7.82-7.90 (m, 1H), 8.08-8.14 (m, 2H), 8.15 (d, J=1.36 Hz, 1H), 8.20 (d,J=1.36 Hz, 1H); MS (ESI) m/z 470 (M+H)⁺.

Example 205(7R,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 203, substituting the product from Example 204 (30 mg, 0.064mmol) for the product from Example 202D. The title compound was obtainedas a colorless solid (23 mg, 76%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.28(s, 3H), 1.30 (s, 3H), 1.78-1.93 (m, 1H), 1.93-2.03 (m, 1H), 2.36 (dd,J=10.00, 5.26 Hz, 1H), 2.40-2.62 (m, 2H), 2.64-2.77 (m, 1H), 2.95-3.14(m, 3H), 3.70 (dd, J=10.00, 6.61 Hz, 1H), 3.86-3.99 (m, 1H), 4.02-4.13(m, 1H), 5.28-5.41 (m, 1H), 7.82-7.89 (m, J=5.76, 3.05 Hz, 1H), 7.91 (d,J=1.36 Hz, 1H), 8.08-8.17 (m, 3H); MS (ESI) m/z 472 (M+H)⁺.

Example 206(7R,8aS)-7-{[5-(1-methylcyclopropyl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazineExample 206A tert-butyl(7R,8aS)-7-{[5-(1-methylcyclopropyl)pyrazin-2-yl]oxy}-hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of the product from Example 202B (40 mg, 0.111 mmol) inanhydrous tetrahydrofuran (1 mL) was added a 0.67 M solution ofdiazomethane in diethyl ether. The yellow solution was cooled to 0° C.,and palladium(II) acetate (1 mg, 4.45 μmol) was added resulting in rapidgas evolution. More diazomethane solution (1 mL) was added dropwise, andthe mixture was stirred at 0° C. for 30 minutes. The addition of 1 mLdiazomethane solution was repeated several more times at 0° C. whilemonitoring reaction progress by LCMS (C18 silica gel using a 3 minutegradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid)).The reaction mixture was concentrated in vacuo and purified by columnchromatography on silica gel using a solvent gradient of 0-50% ethylacetate in hexanes. The title compound was obtained as a colorless oilthat crystallized on standing (30 mg, 72%).

Example 206B(7R,8aS)-7-{[5-(1-methylcyclopropyl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

To a solution of the product from Example 206A (28 mg, 0.075 mmol) in1,4-dioxane (1 mL) was added a 4 M solution of hydrogen chloride in1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred atroom temperature for 90 minutes, and the mixture was then concentratedand dried in vacuo. To the resulting colorless solid was added CH₂Cl₂(0.75 mL), diisopropylethylamine (0.065 mL, 0.375 mmol) and3-(trifluoromethyl)benzene-1-sulfonyl chloride (22.02 mg, 0.090 mmol).The resulting mixture was stirred at room temperature for 3 hours. Themixture was partitioned between water and CH₂Cl₂, and the organic layerwas dried over Na₂SO₄. The drying agent was removed by filtration, andthe filtrate was concentrated in vacuo. The crude product was purifiedby column chromatography on silica gel using a solvent gradient of 0-40%ethyl acetate in hexanes. The title compound was obtained as a colorlesssolid (10 mg, 28%). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.72-0.81 (m, 2H),1.07-1.17 (m, 2H), 1.48 (s, 3H), 1.72-1.88 (m, 1H), 1.92-2.05 (m, 1H),2.12 (t, J=10.51 Hz, 1H), 2.33 (dd, J=9.92, 5.16 Hz, 1H), 2.38-2.63 (m,3H), 2.94-3.07 (m, 1H), 3.65 (dd, J=10.31, 6.74 Hz, 1H), 3.72-3.82 (m,1H), 3.86-3.98 (m, 1H), 5.23-5.35 (m, 1H), 7.70 (t, J=7.93 Hz, 1H), 7.87(d, J=7.93 Hz, 1H), 7.96 (d, J=7.93 Hz, 1H), 8.00 (d, J=1.19 Hz, 1H),8.01-8.04 (m, 1H), 8.05 (d, J=1.19 Hz, 1H); MS (ESI) m/z 483 (M+H)⁺.

Example 2077-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-oneExample 207A tert-butyl6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a suspension of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-onehydrochloride (0.50 g, 2.83 mmol) in CH₂Cl₂ (25 mL) was addeddi-tert-butyl-dicarbonate (0.741 g, 3.41 mmol) and triethylamine (0.79mL, 5.66 mmol). The resulting mixture was stirred at room temperaturefor 3 hours. The mixture was partitioned between water and CH₂Cl₂, andthe organic layer was dried over Na₂SO₄. The drying agent was removed byfiltration, and the filtrate was concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel using asolvent gradient of 0-5% methanol in CH₂Cl₂ to give the title compound(0.58 g, 85%).

Example 207B tert-butyl7-hydroxy-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of the product from Example 207A (0.20 g, 0.832 mmol) inanhydrous tetrahydrofuran (6 mL) at −78° C. under N₂ was added a 1 Msolution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.25mL, 1.25 mmol). The resulting mixture was stirred at −78° C. for 20minutes, and then a solution of3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.326 g, 1.248 mmol) inanhydrous tetrahydrofuran (3 mL) was added dropwise. The mixture wasstirred at −78° C. for 20 minutes and then warmed to −40° C. and stirredfor 2 hours. A solution of NH₄Cl (10% in water, 2 mL) was added, and themixture was allowed to warm to room temperature and partitioned betweenwater and ethyl acetate (5×). The combined organic layers were driedover Na₂SO₄. The drying agent was removed by filtration, and thefiltrate was concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel using a solvent gradient of 0-10%CH₃OH in CH₂Cl₂ to give the title compound (89 mg, 42%).

Example 207C tert-butyl7-[(5-cyclopropylpyrazin-2-yl)oxy]-6-oxohexahydropyrrolo[1,2-a]-pyrazine-2(1H)-carboxylate

To a solution of the product from Example 207B (89 mg, 0.347 mmol) inanhydrous acetonitrile (3.5 mL) was added cesium carbonate (226 mg,0.695 mmol) and 2-bromo-5-cyclopropylpyrazine (104 mg, 0.521 mmol). Theresulting mixture was stirred under N₂ at 50° C. for 48 hours. Themixture was allowed to cool to room temperature and partitioned betweenwater and ethyl acetate (3×). The combined organic layers were driedover Na₂SO₄. The drying agent was removed by filtration, and thefiltrate was concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel using a solvent gradient of 0-10%CH₃OH in CH₂Cl₂ to give the title compound (82 mg, 63%).

Example 207D7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

To a solution of the product from Example 207C (40 mg, 0.107 mmol) in1,4-dioxane (0.5 mL) was added a 4 M solution of hydrogen chloride in1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred atroom temperature for 90 minutes and then concentrated in vacuo. To theresidue was added CH₂Cl₂ (1 mL), 3-(trifluoromethyl)-benzene-1-sulfonylchloride (0.021 mL, 0.130 mmol) and triethylamine (0.045 mL, 0.324mmol), and the resulting mixture was stirred at room temperature for 90minutes. The mixture was partitioned between water and CH₂Cl₂, and theorganic layer was dried over Na₂SO₄. The drying agent was removed byfiltration, and the filtrate was concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel using asolvent gradient of 0-5% CH₃OH in CH₂Cl₂ to give the title compound (47mg, 90%). 1H NMR (300 MHz, CDCl₃) δ ppm 0.84-1.04 (m, 4H) 1.55-1.65 (m,0.6H) 1.89-2.50 (m, 4H) 2.85-2.98 (m, 0.4H) 3.00-3.20 (m, 1H) 3.69-3.84(m, 0.4H) 3.83-3.96 (m, 1.6H) 3.95-4.07 (m, 1H) 4.20 (dd, J=13.22, 2.37Hz, 1H) 5.43 (dd, J=8.14, 5.09 Hz, 0.6H) 5.57 (t, J=7.63 Hz, 0.4H) 7.74(t, J=7.80 Hz, 1H) 7.86-7.99 (m, 3H) 8.00-8.04 (m, 1H) 8.07-8.13 (m,1H); MS (ESI) m/z 483 (M+H)⁺.

Example 208(7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The product from Example 207D was subjected to chiral chromatography(Chiracel® OJ-H column), eluted with 10-50% CH₃OH in supercritical CO₂.The title compound was the first of four stereoisomers to elute. ¹H NMR(300 MHz, CDCl₃) δ ppm 0.89-1.01 (m, 4H) 1.92-2.39 (m, 5H) 3.06-3.21 (m,1H) 3.82-3.97 (m, 2H) 3.97-4.05 (m, 1H) 4.20 (dd, J=13.56, 2.37 Hz, 1H)5.43 (dd, J=8.14, 4.75 Hz, 1H) 7.74 (t, J=7.97 Hz, 1H) 7.88-7.98 (m, 3H)8.02 (s, 1H) 8.12 (d, J=1.36 Hz, 1H).

Example 209(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The product from Example 207D was subjected to chiral chromatography(Chiracel® OJ-H column), eluted with 10-50% CH₃OH in supercritical CO₂.The title compound was the second of four stereoisomers to elute. ¹H NMR(500 MHz, CDCl₃) δ ppm 0.89-1.00 (m, 4H) 1.57-1.64 (m, 1H) 1.93-2.02 (m,1H) 2.15 (t, J=10.99 Hz, 1H) 2.37-2.47 (m, 1H) 2.87-2.97 (m, 1H)3.03-3.12 (m, 1H) 3.73-3.84 (m, 1H) 3.87-3.94 (m, 1H) 3.97-4.05 (m, 1H)4.20 (dd, J=13.43, 2.44 Hz, 1H) 5.57 (t, J=8.24 Hz, 1H) 7.74 (t, J=7.93Hz, 1H) 7.88 (d, J=1.22 Hz, 1H) 7.92 (d, J=7.63 Hz, 1H) 7.95 (d, J=7.93Hz, 1H) 8.02 (s, 1H) 8.09 (d, J=1.53 Hz, 1H).

Example 210(7R,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The product from Example 207D was subjected to chiral chromatography(Chiracel® OJ-H column), eluted with 10-50% CH₃OH in supercritical CO₂.The title compound was the third of four stereoisomers to elute. ¹H NMR(500 MHz, CDCl₃) δ ppm 0.88-1.01 (m, 4H) 1.56-1.63 (m, 2H) 1.94-2.02 (m,1H) 2.15 (t, J=11.14 Hz, 1H) 2.37-2.47 (m, 1H) 2.87-2.97 (m, 1H)3.74-3.82 (m, 1H) 3.87-3.93 (m, 1H) 4.00 (dd, J=11.60, 2.44 Hz, 1H) 4.20(dd, J=13.43, 2.75 Hz, 1H) 5.57 (t, J=8.24 Hz, 1H) 7.74 (t, J=7.78 Hz,1H) 7.88 (s, 1H) 7.91 (d, J=7.93 Hz, 1H) 7.95 (d, J=7.93 Hz, 1H) 8.02(s, 1H) 8.09 (s, 1H).

Example 211(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The product from Example 207D was subjected to chiral chromatography(Chiracel® OJ-H column), eluted with 10-50% CH₃OH in supercritical CO₂.The title compound was the fourth of four stereoisomers to elute. ¹H NMR(500 MHz, CDCl₃) δ ppm 0.90-1.02 (m, 4H) 1.94-2.03 (m, 1H) 2.07 (t,J=10.99 Hz, 1H) 2.15-2.40 (m, 3H) 3.08-3.20 (m, 1H) 3.84-3.96 (m, 2H)3.97-4.06 (m, 1H) 4.20 (d, J=12.82 Hz, 1H) 5.43 (dd, J=8.24, 4.58 Hz,1H) 7.74 (t, J=7.78 Hz, 1H) 7.89-7.94 (m, 2H) 7.96 (d, J=7.63 Hz, 1H)8.02 (s, 1H) 8.12 (s, 1H).

Example 2127-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The title compound was prepared according to the procedure described inExample 207D, substituting 4-(trifluoromethyl)benzene-1-sulfonylchloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (300MHz, CDCl₃) δ ppm 0.87-1.02 (m, 4H) 1.54-1.65 (m, 0.6H) 1.90-2.48 (m,4H) 2.84-2.98 (m, 0.4H) 2.99-3.20 (m, 1H) 3.70-3.82 (m, 0.4H) 3.82-3.96(m, 1.6H) 3.96-4.05 (m, 1H) 4.19 (dd, J=13.22, 2.37 Hz, 1H) 5.43 (dd,J=8.31, 4.92 Hz, 0.6H) 5.51-5.62 (m, 0.4H) 7.80-7.94 (m, 5H) 8.07-8.14(m, 1H); MS (ESI) m/z 483 (M+H)⁺.

Example 213(8aS)-7-(3-fluorobenzyl)-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-oneExample 213A tert-butyl(8aS)-7-(3-fluorobenzyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of the product from Example 207A (0.10 g, 0.416 mmol) inanhydrous tetrahydrofuran (4 mL) at −78° C. under N₂ was added a 1 Msolution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.458mL, 0.458 mmol) dropwise over 2 minutes. To the resulting solution wasadded 1-(bromomethyl)-3-fluorobenzene (0.056 mL, 0.458 mmol), and theresulting mixture was stirred at −40° C. for 3 hours. A solution ofNH₄Cl (10% in water, 1 mL) was added, and the mixture was allowed towarm to room temperature and partitioned between water and ethyl acetate(3×). The combined organic layers were dried over Na₂SO₄. The dryingagent was removed by filtration, and the filtrate was concentrated invacuo. The crude product was purified by column chromatography on silicagel using a solvent gradient of 0-10% CH₃OH in CH₂Cl₂ to give the titlecompound (75 mg, 52%).

Example 213B(8aS)-7-(3-fluorobenzyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-onehydrochloride

To a solution of the product from Example 213A (72 mg, 0.207 mmol) in1,4-dioxane (1 mL) was added a 4 M solution of hydrogen chloride in1,4-dioxane (1 mL, 4.0 mmol). The resulting mixture was stirred at roomtemperature for 90 minutes and concentrated and dried in vacuo to givethe title compound (59 mg, quantitative).

Example 213C(8aS)-7-(3-fluorobenzyl)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The product from Example 213B (20 mg, 0.070 mmol) was suspended inCH₂Cl₂ (0.5 mL), 4-(trifluoromethyl)benzene-1-sulfonyl chloride (21 mg,0.084 mmol) and triethylamine (0.049 mL, 0.35 mmol) were added, and theresulting mixture was stirred at room temperature for 90 minutes. Themixture was partitioned between water and CH₂Cl₂, and the organic layerwas dried over Na₂SO₄. The drying agent was removed by filtration, andthe filtrate was concentrated in vacuo. The crude product was purifiedby column chromatography on silica gel using a solvent gradient of 0-5%CH₃OH in CH₂Cl₂ to give the title compound (30 mg, 94%). ¹H NMR (300MHz, CDCl₃) δ ppm 1.16-1.51 (m, 1H) 1.59-1.72 (m, 1H) 1.88-2.03 (m, 1H)2.09-2.32 (m, 1H) 2.64-3.12 (m, 4H) 3.27-3.64 (m, 1H) 3.73-3.86 (m, 2H)4.11 (dd, J=13.22, 2.37 Hz, 1H) 6.68-6.98 (m, 3H) 7.08-7.29 (m, 1H)7.77-7.89 (m, 4H); MS (ESI) m/z 457 (M+H)⁺.

Example 214(8aS)-7-(3-fluorobenzyl)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The product from Example 213B (38 mg, 0.133 mmol) was subjected to theprocedure described for Example 213C, substituting3-(trifluoromethyl)benzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. The title compound wasobtained as a colorless solid (45 mg, 74%). ¹H NMR (300 MHz, CDCl₃) δppm 1.16-1.51 (m, 1H) 1.59-1.74 (m, 1H) 1.88-2.03 (m, 1H) 2.10-2.32 (m,1H) 2.65-3.13 (m, 4H) 3.26-3.65 (m, 1H) 3.74-3.87 (m, 2H) 4.12 (dd,J=13.39, 2.20 Hz, 1H) 6.65-6.99 (m, 3H) 7.09-7.30 (m, 1H) 7.66-7.77 (m,1H) 7.85-8.01 (m, 3H); MS (ESI) m/z 457 (M+H)⁺.

Example 215(7S,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-oneExample 215A

tert-butyl(7S,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

The title compound was prepared according to the procedure described inExample 213A substituting 3-fluorobenzaldehyde for1-(bromomethyl)-3-fluorobenzene. The title compound was the first of twostereoisomers to elute during chromatography.

Example 215B(7S,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The product from Example 215A (64 mg, 0.176 mmol) was subjected to theprocedures described for Example 213B and Example 213C substituting3-(trifluoromethyl)benzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. The title compound wasobtained as a colorless solid (33 mg, 40%). ¹H NMR (300 MHz, CDCl₃) δppm 1.36-1.66 (m, 1H) 1.76-2.03 (m, 2H) 2.13-2.36 (m, 1.5H) 2.64-2.83(m, 1H) 2.85-3.07 (m, 1.5H) 3.46-3.70 (m, 1H) 3.75-3.92 (m, 2H)4.08-4.21 (m, 1H) 5.28 (dd, J=5.09, 3.05 Hz, 1H) 6.79-7.16 (m, 3H)7.17-7.37 (m, 1H) 7.64-7.80 (m, 1H) 7.83-8.02 (m, 3H); MS (ESI) m/z 473(M+H)⁺.

Example 216(7R,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-oneExample 216A tert-butyl(7R,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

The title compound was prepared according to the procedure described inExample 213A, substituting 3-fluorobenzaldehyde for1-(bromomethyl)-3-fluorobenzene. The title compound was the second oftwo stereoisomers to elute during chromatography.

Example 216B(7R,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The product from Example 216A (24 mg, 0.066 mmol) was subjected to theprocedures described for Example 213B and Example 213C substituting3-(trifluoromethyl)benzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. The title compound wasobtained as a colorless solid (7 mg, 22%). ¹H NMR (300 MHz, CDCl₃) δ ppm1.43-1.52 (m, 1H) 1.85-2.04 (m, 2H) 2.21-2.32 (m, 1H) 2.63-2.75 (m, 1H)2.94-3.07 (m, 1H) 3.47-3.59 (m, 1H) 3.75-3.86 (m, 2H) 4.09-4.19 (m, 1H)4.58 (s, 1H) 4.73 (d, J=8.82 Hz, 1H) 6.95-7.05 (m, 1H) 7.05-7.12 (m, 2H)7.26-7.36 (m, 1H) 7.71 (t, J=7.80 Hz, 1H) 7.90 (d, J=7.80 Hz, 2H) 7.97(s, 1H); MS (ESI) m/z 473 (M+H)⁺.

Example 2172-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)pyridin-2-yl]-oxy}hexahydropyrrolo[1,2-a]pyrazin-6(211)-oneExample 217A2-{[3-(trifluoromethyl)phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(211)-one

To a solution of hexahydropyrrolo[1,2-a]pyrazin-6(211)-one hydrochloride(0.1 g, 0.566 mmol) in CH₂Cl₂ (5 mL) was added triethylamine (0.237 mL,1.698 mmol) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.109mL, 0.679 mmol). The resulting mixture was stirred at room temperaturefor 90 minutes, after which time it was partitioned between water (10mL) and CH₂Cl₂ (2×10 mL). The combined organic layer was dried overNa₂SO₄. The crude product was purified by column chromatography onsilica gel using a solvent gradient of 0-5% CH₃OH in CH₂Cl₂ to give thetitle compound as a colorless solid (0.169 mg, 86%).

Example 217B7-hydroxy-2-{[3-(trifluoromethyl)phenyl]sulfonyl}hexahydropyrrolo[1,2-a]-pyrazin-6(2H)-one

To a solution of the product from Example 217A (98 mg, 0.281 mmol) inanhydrous tetrahydrofuran (2 mL) at −78° C. under N₂ was added lithiumbis(trimethylsilyl)amide (1 M in tetrahydrofuran) (0.422 mL, 0.422mmol). The resulting mixture was stirred at −78° C. for 20 minutes, andthen a solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (147 mg,0.563 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise. Oncethe addition was complete, the mixture was warmed to −40° C. and stirredfor 2 hours. A solution of NH₄Cl (10% in water, 2 mL) was added, and themixture was allowed to warm to room temperature and partitioned betweenwater and ethyl acetate (5×). The combined organic layers were driedover Na₂SO₄. The drying agent was removed by filtration, and thefiltrate was concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel using a solvent gradient of 0-5%CH₃OH in CH₂Cl₂ to give the title compound (24 mg, 23%).

Example 217C2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)pyridin-2-yl]-oxy}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

To a solution of the product from Example 217B (23 mg, 0.063 mmol) inanhydrous N,N-dimethylformamide (0.6 mL) at 0° C. was added sodiumhydride (60% suspension in mineral oil, 2.78 mg, 0.069 mmol). Theresulting mixture was stirred at 0° C. for 10 minutes, and2-bromo-5-(trifluoromethyl)pyridine (21 mg, 0.095 mmol) was added. Theresulting mixture was allowed to warm to room temperature and stirredfor 3 hours. The mixture was partitioned between water and ethyl acetate(3×), and the combined organic layers were concentrated in vacuo andpurified on C18 silica gel using a solvent gradient of 0-100%acetonitrile in water (0.1% trifluoroacetic acid). The title compoundwas obtained as a colorless solid (22 mg, 68%). ¹H NMR (300 MHz, CDCl₃)δ ppm 1.58-1.68 (m, 0.5H) 2.03-2.49 (m, 3H) 2.88-3.21 (m, 1.5H)3.72-4.08 (m, 3H) 4.21 (dd, J=13.39, 3.22 Hz, 1H) 5.50-5.74 (m, 1H) 6.88(t, J=8.82 Hz, 1H) 7.69-7.85 (m, 2H) 7.88-8.00 (m, 2H) 8.02 (s, 1H)8.26-8.43 (m, 1H); MS (ESI) m/z 510 (M+H)⁺.

Example 218(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-benzyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared according to the procedure described inExample 57, substituting (3-(trifluoromethyl)phenyl)methanesulfonylchloride for 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride. ¹H NMR(300 MHz, CDCl₃) δ ppm 0.85-1.04 (m, 4H) 1.75-1.90 (m, 3H) 2.20-2.60 (m,4H) 2.76-3.11 (m, 2H) 3.54-3.87 (m, 3H) 4.26 (s, 2H) 5.24-5.43 (m, 1H)7.48-7.70 (m, 4H) 7.92 (d, J=1.36 Hz, 1H) 8.03 (d, J=1.36 Hz, 1H); MS(ESI) m/z 483 (M+H)⁺.

Example 219(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4,4,4-trifluorobutyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine

The procedures for Example 17E and Example 18 were used substituting(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for(7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol and substituting4,4,4-trifluorobutane-1-sulfonyl chloride for3-(trifluoromethyl)benzene-1-sulfonyl chloride to give the titlecompound (53% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87(m, 4H), 1.86 (m, 4H), 2.36 (m, 4H), 2.60 (m, 2H), 2.90 (m, 1H), 3.10(m, 4H), 3.54 (m, 1H), 3.63 (m, 1H), 3.70 (m, 1H), 5.27 (m, 1H), 8.13(s, 2H); MS (ESI) m/z 435 (M+H)⁺.

Example 220(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-4(1H)-oneExample 220A tert-butyl(2S,4R)-4-hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-pyrrolidine-1-carboxylate

tert-Butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate(500 mg; 2.3 mmol) in pyridine (20 mL) was cooled to 0° C. To thiscooled solution was added a solution of p-toluenesulfonyl chloride (483mg, 2.53 mmol) in pyridine (5 mL) over a period of 1 hour. The reactionmixture was allowed to slowly warm to ambient temperature and stirringwas continued at ambient for 48 hours. The volatiles were removed invacuo, and the residue was redissolved in toluene and concentrated againin vacuo. The crude material was triturated with ethyl acetate. This wasfurther purified by chromatography on a 12 g silica gel column elutedwith 5% ethyl acetate/hexanes for 3 minutes and then eluted with agradient to 100% ethyl acetate over 20 minutes. The title compound wasisolated as an oil (397 mg; 64% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm7.82-7.69 (m, 2H), 7.48 (d, J=7.9 Hz, 2H), 4.92 (d, J=2.8 Hz, 1H),4.23-3.82 (m, 4H), 3.12 (dd, J=25.5, 13.9 Hz, 2H), 2.42 (d, J=3.6 Hz,3H), 1.87 (d, J=20.3 Hz, 2H), 1.35 (dd, J=23.0, 13.0 Hz, 9H).

Example 220B tert-butyl(2S,4R)-2-(azidomethyl)-4-hydroxypyrrolidine-1-carboxylate

To a solution of Example 220A (365 mg, 1.021 mmol) inN,N-dimethylformamide (5 mL) was added sodium azide (531 mg, 8.17 mmol).The reaction mixture was stirred at 55° C. for 8 hours. Chromatographyon a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3minutes followed by a gradient to 100% ethyl acetate over 20 minutesprovided the title compound (135 mg, 0.557 mmol, 54.6% yield) as an oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.65 (d, J=3.5 Hz, 1H), 4.24 (d, J=3.5Hz, 1H), 3.97 (ddd, J=10.2, 7.6, 3.1 Hz, 1H), 3.64 (dd, J=12.3, 5.5 Hz,1H), 3.39-3.22 (m, 3H), 2.01-1.80 (m, 2H), 1.42 (s, 9H); MS (DCI) m/z243 (M+H)⁺.

Example 220C tert-butyl(2S,4R)-2-(azidomethyl)-4-[(5-cyclopropylpyrazin-2-yl)oxy]-pyrrolidine-1-carboxylate

To a solution of Example 220B (98 mg, 0.404 mmol) in tetrahydrofuran (1mL) was added potassium t-butoxide (63.5 mg, 0.566 mmol) followed byaddition of 2-bromo-5-cyclopropylpyrazine (Combi-Phos Inc) (89 mg, 0.445mmol). The reaction mixture was stirred at room temperature for 24hours. The mixture was diluted with water and extracted with ethylacetate (2×20 mL). Volatiles were removed with a stream of nitrogen. Theresidue was chromatographed on a 12 g SiO₂ column eluted with 5% ethylacetate/hexanes for 3 minutes and then with a gradient to 100% ethylacetate over 20 minutes. The title compound (87 mg, 0.241 mmol, 59.7%yield) was isolated as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) 8 ppm8.09 (d, J=1.3 Hz, 1H), 8.06 (d, J=1.3 Hz, 1H), 5.44-5.39 (m, 1H),4.12-4.04 (m, 1H), 3.71 (dd, J=12.4, 5.3 Hz, 1H), 3.64 (d, J=12.3 Hz,1H), 3.57 (dd, J=12.4, 4.6 Hz, 1H), 3.39 (dd, J=12.4, 3.2 Hz, 1H),2.30-2.06 (m, 3H), 1.41 (s, 9H), 0.97-0.90 (m, 2H), 0.87-0.81 (m, 2H).

Example 220D tert-butyl(2S,4R)-2-(aminomethyl)-4-[(5-cyclopropylpyrazin-2-yl)oxy]-pyrrolidine-1-carboxylate

Example 220C (2.54 g, 7.05 mmol) was dissolved in methanol containing 7M ammonia (30 mL). The resulting solution was added to Raney®-nickel2800/water, that had been washed once with methanol to remove excesswater, in a stainless steel container (250 mL). The mixture was shakenfor 4 hours under hydrogen (30 psi). The resulting slurry was filteredthrough a 0.45 μm nylon membrane, and the solvents were removed invacuo. The resulting green viscous oil was carried on without additionalpurification.

Example 220E tert-butyl(2S,4R)-4-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[(2-methoxy-2-oxoethyl)amino]methyl}pyrrolidine-1-carboxylate

Example 220E (361 mg, 1.080 mmol) was dissolved in methanol (2 mL).Triethylamine (331 μL, 2.375 mmol) was added followed by addition ofmethyl 2-bromoacetate (110 μL, 1.187 mmol). The mixture was stirred at65° C. for 3 hours. Chromatography on a 24 g SiO₂ column eluted with 5%ethyl acetate/hexanes for 3 minutes and then with a gradient to 100%ethyl acetate over 20 minutes provided the title compound (185 mg, 0.455mmol, 42.2% yield) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.13 (dd, J=11.8, 1.3 Hz, 2H), 5.36 (s, 1H), 3.90 (s, 1H), 3.63-3.48 (m,6H), 2.72 (s, 2H), 2.14 (ddd, J=23.5, 13.0, 12.5 Hz, 4H), 1.37 (s, 10H),1.00-0.87 (m, 2H), 0.85-0.76 (m, 2H); MS (ESI) m/z 407 (M+H)⁺.

Example 220F tert-butyl(2S,4R)-4-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[(2-methoxy-2-oxoethyl){[3-(trifluoromethyl)phenyl]sulfonyl}amino]methyl}pyrrolidine-1-carboxylate

Example 220E (92 mg, 0.226 mmol) was dissolved in methylene chloride (1mL). Triethylamine (63.1 μL, 0.453 mmol) and3(trifluoromethyl)benzenesulfonyl chloride (39.9 μL, 0.249 mmol) weresequentially added. The reaction mixture was stirred at ambienttemperature for 2 hours. Chromatography on a 12 g SiO₂ column elutedwith 5% ethyl acetate/hexanes for 3 minutes and then with a gradient to100% ethyl acetate over 20 minutes afforded the title compound (101 mg,0.164 mmol, 72.6% yield) as a viscous oil. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.22-8.01 (m, 5H), 7.85 (t, J=7.8 Hz, 1H), 5.36 (s, 1H), 4.39-4.15(m, 2H), 4.15-4.04 (m, 1H), 3.56 (dd, J=46.9, 17.5 Hz, 6H), 3.38 (s,1H), 2.30-2.08 (m, 3H), 1.33 (d, J=6.0 Hz, 9H), 0.97-0.92 (m, 2H),0.86-0.80 (m, 2H); MS (ESI) m/z 515 (M-t-Bu+H)⁺.

Example 220G methylN-({(2S,4R)-4-[(5-cyclopropylpyrazin-2-yl)oxy]pyrrolidin-2-yl}-methyl)-N-{[3-(trifluoromethyl)phenyl]sulfonyl}glycinatehydrochloride

Example 220F (99 mg, 0.161 mmol) was dissolved in methylene chloride (25mL). 4 N HCl (1 mL) in dioxane was added, and the reaction mixture wasstirred at ambient temperature for 1 hour. Removal of solvents in vacuoafforded the title compound as a white foam that was used withoutfurther purification.

Example 220H(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one

Example 220G (89 mg, 0.162 mmol) was dissolved in methanol (1 mL) andtreated with triethylamine (90 μL, 0.646 mmol). The mixture was heatedto reflux for 48 hours, cooled to ambient temperature and purified bychromatography on a 12 g SiO₂ column eluted with 5% ethylacetate/hexanes for 3 minutes and then with a gradient to 100% ethylacetate over 20 minutes. The title compound (28.4 mg, 0.059 mmol, 36.4%yield) was isolated as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.24-8.04 (m, 5H), 7.98-7.86 (m, 1H), 5.52-5.41 (m, 1H), 4.20-3.98 (m,2H), 3.95-3.73 (m, 2H), 3.40-3.33 (m, 1H), 3.29-3.22 (m, 1H), 2.76-2.59(m, 1H), 2.32-2.04 (m, 2H), 1.86-1.70 (m, 1H), 1.01-0.88 (m, 2H),0.86-0.74 (m, 2H); MS (ESI) m/z 483 (M+H)⁺.

Example 221(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-4(1H)-oneExample 221A methylN-({(2S,4R)-4-[(5-cyclopropylpyrazin-2-yl)oxy]pyrrolidin-2-yl}-methyl)glycinatehydrochloride

Example 220E (1.10 g, 2.71 mmol) was dissolved in methylene chloride (3mL). 4 M HCl in dioxane (3 mL) was added, and the mixture was stirredfor 30 minutes. The volatiles were removed in vacuo to supply the titlecompound which was used in the next step without further purification.

Example 221B(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one

Example 221A (0.958 g, 2.79 mmol) was dissolved in methanol (10 mL), andtriethylamine was added until the mixture was found to be basic by pHpaper. The mixture was allowed to reflux overnight after which thesolvents were removed in vacuo. Chromatography on a 12 g SiO₂ columneluted with 2.5% methanol (containing 2 N ammonia) in methylene chloridefor 3 minutes and then with a gradient from 0-10% methanol (containing 2N ammonia) in methylene chloride provided the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 8.15 (dd, J=9.2, 1.4 Hz, 2H), 5.47 (t, J=5.0Hz, 1H), 4.05-3.88 (m, 1H), 3.87-3.69 (m, 1H), 3.26-3.01 (m, 4H), 2.67(s, 1H), 2.34 (dd, J=12.7, 10.2 Hz, 1H), 2.24-2.03 (m, 2H), 1.73 (ddd,J=13.3, 11.9, 4.8 Hz, 1H), 1.03-0.88 (m, 2H), 0.82 (ddd, J=6.8, 4.7, 2.4Hz, 2H); MS (ESI) m/z 275 (M+H)⁺.

Example 221C(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one

Example 221B (86 mg, 0.314 mmol) in CH₂Cl₂ (2 mL) was treated withtriethylamine(43.7 μL, 0.314 mmol) and4-(trifluoromethyl)benzene-1-sulfonyl chloride (84 mg, 0.345 mmol). Themixture was stirred at ambient temperature for 18 hours. Chromatographyon a 12 g SiO₂ column eluted with 5% ethyl acetate/hexanes for 3 minutesand then with a gradient to 100% ethyl acetate over 20 minutes furnishedthe title compound (31 mg, 0.064 mmol, 20.49% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.31 (s, 1H), 8.21-7.96 (m, 5H), 5.47(t, J=4.7 Hz, 1H), 4.17-3.96 (m, 4H), 3.93-3.75 (m, 2H), 2.66 (dd,J=24.2, 12.4 Hz, 1H), 2.25 (dd, J=13.5, 4.5 Hz, 1H), 2.11 (td, J=8.2,4.1 Hz, 1H), 1.84-1.70 (m, 1H), 1.02-0.76 (m, 4H); MS (ESI) m/z 483(M+H)⁺.

Example 222(8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The title compound was prepared according to the procedures for Example207, substituting (R)-hexahydropyrrolo[1,2-a]pyrazin-6(7H)-onehydrochloride for hexahydropyrrolo[1,2-a]pyrazin-6(2H)-onehydrochloride. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.84-1.04 (m, 4H) 1.54-1.65(m, 0.65H) 1.89-2.50 (m, 4H) 2.85-2.99 (m, 0.35H) 3.00-3.20 (m, 1H)3.68-3.84 (m, 0.35H) 3.83-3.96 (m, 1.65H) 3.95-4.07 (m, 1H) 4.20 (dd,J=13.22, 2.37 Hz, 1H) 5.43 (dd, J=8.14, 4.75 Hz, 0.65H) 5.53-5.61 (m,0.35H) 7.74 (t, J=7.80 Hz, 1H) 7.86-7.99 (m, 3H) 8.00-8.05 (m, 1H)8.07-8.14 (m, 1H); MS (ESI) m/z 483 (M+H)⁺.

Example 223(8aS)-7-[3-(trifluoromethyl)benzyl]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The title compound was prepared according to the procedures describedfor Example 213, substituting 1-(bromomethyl)-3-(trifluoromethyl)benzenefor 1-(bromomethyl)-3-fluorobenzene and substituting3-(trifluoromethyl)benzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. NMR indicates a 4:1ratio of trans:cis isomers. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.59-1.76 (m,1H) 1.89-2.01 (m, 1.8H) 2.06-2.19 (m, 0.2H) 2.20-2.32 (m, 1H) 2.67-2.99(m, 3H) 3.07-3.17 (m, 1H) 3.26-3.39 (m, 0.8H) 3.51-3.65 (m, 0.2H)3.74-3.87 (m, 2H) 4.06-4.18 (m, 1H) 7.29-7.54 (m, 4H) 7.66-7.76 (m, 1H)7.85-7.99 (m, 3H); MS (ESI) m/z 507 (M+H)⁺.

Example 224(8aS)-7-[3-(trifluoromethyl)benzyl]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

The title compound was prepared according to the procedures describedfor Example 213, substituting 1-(bromomethyl)-3-(trifluoromethyl)benzenefor 1-(bromomethyl)-3-fluorobenzene. NMR indicates a 4:1 ratio oftrans:cis isomers. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.59-1.75 (m, 1H)1.87-2.02 (m, 1.8H) 2.04-2.18 (m, 0.2H) 2.19-2.34 (m, 1H) 2.68-2.98 (m,3H) 3.12 (dd, J=13.56, 4.07 Hz, 1H) 3.25-3.40 (m, 0.8H) 3.52-3.67 (m,0.2H) 3.72-3.87 (m, 2H) 4.05-4.19 (m, 1H) 7.28-7.55 (m, 4H) 7.76-7.89(m, 4H); MS (ESI) m/z 507 (M+H)⁺.

Example 2253-{[(8aS)-6-oxo-7-[3-(trifluoromethyl)benzyl]hexahydropyrrolo[1,2-a]-pyrazin-2(1H)-yl]sulfonyl}benzonitrile

The title compound was prepared according to the procedures describedfor Example 213, substituting 1-(bromomethyl)-3-(trifluoromethyl)benzenefor 1-(bromomethyl)-3-fluorobenzene and substituting3-cyanobenzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. NMR indicates a 4:1ratio of trans:cis isomers. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.63-1.77 (m,1H) 1.88-2.04 (m, 1.8H) 2.07-2.19 (m, 0.2H) 2.21-2.33 (m, 1H) 2.68-3.01(m, 3H) 3.08-3.17 (m, 1H) 3.26-3.39 (m, 0.8H) 3.53-3.66 (m, 0.2H)3.73-3.86 (m, 2H) 4.06-4.19 (m, 1H) 7.32-7.55 (m, 4H) 7.65-7.75 (m, 1H)7.87-8.02 (m, 3H); MS (ESI) m/z 464 (M+H)⁺.

Example 226(7R,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)-pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazineExample 226A tert-butyl(7R,8aS)-7-{[5-(trifluoromethyl)pyridin-2-yl]oxy}hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

To a solution of the product from Example 202A (0.20 g, 0.825 mmol) inanhydrous tetrahydrofuran (8 mL) was added a 1.0 M solution of potassiumtert-butoxide in tetrahydrofuran (0.825 mL, 0.825 mmol), followed by2-bromo-5-(trifluoromethyl)pyridine. The resulting mixture was stirredat room temperature for 3 hours, and then it was partitioned betweenwater and ethyl acetate (3×). The organic extracts were combined anddried over Na₂SO₄. The crude product was purified by columnchromatography on silica gel using a solvent gradient of 0-5% CH₃OH inCH₂Cl₂ to give the title compound as a colorless solid (0.28 g, 88%).

Example 226B(7R,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)-pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

A solution of the product from Example 226A (0.14 g, 0.361 mmol) indichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was stirredat room temperature for 2 hours and then concentrated in vacuo. Theresidue was dissolved in a mixture of dichloromethane (3 mL) andtriethylamine (0.30 mL, 2.17 mmol), and4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.097 g, 0.398 mmol) wasadded. The resulting mixture was stirred at room temperature for 16hours, and then it was partitioned between water and dichloromethane.The organic extract was dried over Na₂SO₄. The crude product waspurified by column chromatography on silica gel using a solvent gradientof 0-3% ethyl acetate in heptane to give the title compound as acolorless solid (0.132 g, 74%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.72-1.90(m, 1H) 1.91-2.06 (m, 1H) 2.06-2.20 (m, 1H) 2.33 (dd, J=9.49, 4.75 Hz,1H) 2.37-2.70 (m, 3H) 3.00 (d, J=7.80 Hz, 1H) 3.58-3.73 (m, 1H) 3.77 (d,J=8.82 Hz, 1H) 3.92 (d, J=10.17 Hz, 1H) 5.41 (q, J=6.22 Hz, 1H) 6.79 (d,J=8.82 Hz, 1H) 7.76 (dd, J=8.65, 2.54 Hz, 1H) 7.79-7.94 (m, 4H) 8.39 (d,J=2.37 Hz, 1H); MS (ESI) m/z 496 (M+H)⁺.

Example 2273-{[(7R,8aS)-7-{[5-(trifluoromethyl)pyridin-2-yl]oxy}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile

The title compound was obtained following the procedure described inExample 226B, substituting 3-cyanobenzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃)δ ppm 1.74-1.92 (m, 1H) 1.94-2.07 (m, 1H) 2.15 (t, J=10.34 Hz, 1H) 2.33(dd, J=9.83, 5.09 Hz, 1H) 2.38-2.65 (m, 3H) 3.02 (d, J=9.16 Hz, 1H) 3.68(dd, J=10.00, 6.95 Hz, 1H) 3.77 (d, J=9.16 Hz, 1H) 3.92 (d, J=10.17 Hz,1H) 5.42 (q, J=6.10 Hz, 1H) 6.79 (d, J=8.82 Hz, 1H) 7.69 (t, J=7.80 Hz,1H) 7.77 (dd, J=8.65, 2.20 Hz, 1H) 7.85-7.92 (m, 1H) 7.94-8.03 (m, 1H)8.03-8.10 (m, 1H) 8.39 (d, J=2.37 Hz, 1H); MS (ESI) m/z 453 (M+H)⁺.

Example 228(7R,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

The title compound was obtained according to the procedures describedfor Example 226, substituting 5-fluoro-2-(trifluoromethyl)pyridine for2-bromo-5-(trifluoromethyl)pyridine. ¹H NMR (300 MHz, CDCl₃) δ ppm1.73-1.88 (m, 1H) 2.02 (dd, J=13.43, 5.80 Hz, 1H) 2.14 (t, J=10.38 Hz,1H) 2.37-2.51 (m, 3H) 2.54-2.66 (m, 1H) 2.93-3.09 (m, 1H) 3.63 (dd,J=10.07, 6.71 Hz, 1H) 3.70-3.85 (m, 1H) 3.93 (d, J=10.68 Hz, 1H) 4.87(q, J=6.41 Hz, 1H) 7.20 (dd, J=8.85, 2.75 Hz, 1H) 7.60 (d, J=8.85 Hz,1H) 7.77-7.86 (m, 2H) 7.87-7.95 (m, 2H) 8.30 (d, J=2.75 Hz, 1H); MS(ESI) m/z 496 (M+H)⁺.

Example 2293-{[(7R,8aS)-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile

The title compound was obtained according to the procedures describedfor Example 226 substituting 5-fluoro-2-(trifluoromethyl)pyridine for2-bromo-5-(trifluoromethyl)pyridine and substituting3-cyanobenzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃)8 ppm 1.73-1.90 (m, 1H) 2.01-2.10 (m, 1H) 2.16 (t, J=10.51 Hz, 1H)2.37-2.53 (m, 3H) 2.53-2.67 (m, 1H) 2.93-3.13 (m, 1H) 3.64 (dd, J=9.83,6.78 Hz, 1H) 3.71-3.86 (m, 1H) 3.94 (d, J=10.17 Hz, 1H) 4.88 (q, J=6.22Hz, 1H) 7.20 (dd, J=8.65, 2.88 Hz, 1H) 7.60 (d, J=8.82 Hz, 1H) 7.70 (t,J=7.63 Hz, 1H) 7.85-7.92 (m, 1H) 7.96-8.02 (m, 1H) 8.06 (t, J=1.36 Hz,1H) 8.30 (d, J=2.71 Hz, 1H); MS (ESI) m/z 453 (M+H)⁺.

Example 230(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

The title compound was obtained according to the procedures describedfor Example 226 substituting 2-fluoro-6-(trifluoromethyl)pyridine for2-bromo-5-(trifluoromethyl)pyridine and substituting3-(trifluoromethyl)benzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃)δ ppm 1.74-1.92 (m, 1H) 1.94-2.06 (m, 1H) 2.13 (t, J=10.51 Hz, 1H) 2.32(dd, J=9.83, 5.09 Hz, 1H) 2.38-2.64 (m, 3H) 3.02 (d, J=7.80 Hz, 1H) 3.69(dd, J=9.49, 7.12 Hz, 1H) 3.78 (d, J=8.14 Hz, 1H) 3.92 (d, J=10.51 Hz,1H) 5.28-5.47 (m, 1H) 6.88 (d, J=8.48 Hz, 1H) 7.18-7.24 (m, 1H) 7.70 (t,J=7.97 Hz, 2H) 7.87 (d, J=8.14 Hz, 1H) 7.96 (d, J=7.80 Hz, 1H) 8.03 (s,1H); MS (ESI) m/z 496 (M+H)⁺.

Example 231(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)-pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine

The title compound was obtained according to the procedures describedfor Example 226 substituting 3-fluoro-5-(trifluoromethyl)pyridine for2-bromo-5-(trifluoromethyl)pyridine and substituting3-(trifluoromethyl)benzene-1-sulfonyl chloride for4-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (300 MHz, CDCl₃)δ ppm 1.72-1.90 (m, 1H) 1.97-2.07 (m, 1H) 2.14 (t, J=10.34 Hz, 1H)2.37-2.53 (m, 3H) 2.53-2.69 (m, 1H) 2.92-3.12 (m, 1H) 3.64 (dd, J=9.83,6.78 Hz, 1H) 3.72-3.87 (m, J=8.14 Hz, 1H) 3.94 (d, J=9.83 Hz, 1H) 4.86(q, J=6.44 Hz, 1H) 7.28 (t, J=2.03 Hz, 1H) 7.71 (t, J=7.80 Hz, 1H) 7.88(d, J=8.14 Hz, 1H) 7.97 (d, J=8.14 Hz, 1H) 8.03 (s, 1H) 8.40 (d, J=2.03Hz, 1H) 8.50 (s, 1H); MS (ESI) m/z 496 (M+H)⁺.

Many variations in the invention can suggest themselves to those skilledin the art in light of the foregoing detailed description. All suchobvious variations are within the full intended scope of the appendedclaims.

We claim:
 1. A compound of Formula (I):

or a salt thereof, wherein: Z′ is CH₂ or C(O); Z″ is CH₂; one of R¹ andR² is hydrogen and the other of R¹ and R² is G¹-L¹-; L¹ is—C(R^(c))(R^(d))—, —C(O)NR^(a)—, —NR^(a)C(O)—, —S(O)₂NR^(a)—,—NR^(a)S(O)₂—; —NR^(a)—, or —O—; G¹ is C₁-C₈-alkyl, C₁-C₈-haloalkyl,Ar¹, —(CR^(a)R^(b))_(j)—Ar¹, —CH(Ar¹)₂, or —Ar¹-G^(a); R^(a) and R^(b),at each occurrence, are each independently hydrogen, C₁-C₄-alkyl, orC₁-C₄-haloalkyl; R^(c) and R^(d) are each independently hydrogen,hydroxy, C₁-C₄-alkyl, or C₁-C₄-haloalkyl; j is 1, 2, 3, 4, or 5; Ar¹ is,at each occurrence, independently aryl or heteroaryl, wherein Ar¹ isunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,halogen, cyano, —NO₂, —OR^(s), —OC(O)R^(s), —OC(O)N(R^(s))(R^(t)),—SR^(s), —S(O)R^(s), —S(O)₂R^(s), —S(O)₂N(R^(s))(R^(t)), —C(O)R^(s),—C(O)OR^(s), —C(O)N(R^(s))(R^(t)), —N(R^(s))(R^(t)), —N(R^(s))C(O)R^(t),—N(R^(s))C(O)O(R^(t)), —N(R^(s))S(O)₂(R^(t)), C₁-C₄-cyanoalkyl, andC₁-C₄-haloalkyl; R^(s) and R^(t) are, at each occurrence, independentlyhydrogen, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, or C₁-C₄-haloalkyl;G^(a) is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocyclyl, orheteroaryl, wherein the C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl,heterocyclyl, or heteroaryl are unsubstituted or substituted with 1, 2,or 3 C₁-C₄-alkyl, C₁-C₄-haloalkyl, or halogen; L² is —S(O)₂—,—S(O)₂CH₂—, or —S(O)—; G² is C₁-C₈-alkyl, C₁-C₈-haloalkyl,C₃-C₈-cycloalkyl, Ar² or Ar³; Ar² is aryl or heteroaryl, wherein Ar² isunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,halogen, cyano, —NO₂, -alkyl-OR^(u), —OC(O)R^(u), —OC(O)N(R^(u))(R^(v)),—SR^(u), —S(O)R^(u), —S(O)₂R^(u), —S(O)₂N(R^(u))(R^(v)), —C(O)R^(u),—C(O)OR^(u), —C(O)N(R^(u))(R^(v)), —N(R^(u))(R^(v)), —N(R^(u))C(O)R^(v),—N(R^(u))C(O)O(R^(v)), —N(R^(u))S(O)₂(R^(v)), C₁-C₄-cyanoalkyl,C₁-C₄-haloalkyl, and -G^(b); G^(b) is C₃-C₇-cycloalkyl,C₃-C₇-cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein theC₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, heterocyclyl, aryl, or heteroarylare unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl,C₁-C₄-haloalkyl, or halogen; R^(u) and R^(v) are, at each occurrence,independently hydrogen, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, orC₁-C₄-haloalkyl; Ar³ is (i), wherein:

X is O, S, NR^(w), or CH₂; wherein R^(w) is hydrogen or alkyl; Y is C(O)or CH₂; R^(z) and R^(y) are independently, at each occurrence, hydrogenor C₁-C₄-alkyl; and m is 1, 2 or
 3. 2. The compound of claim 1, or asalt thereof, wherein: Z′ is CH₂; R¹ is G¹-L¹-; and R² is hydrogen. 3.The compound of claim 1, or a salt thereof, wherein: Z′ is C(O); R¹ isG¹-L¹-; and R² is hydrogen.
 4. The compound of claim 1, or a saltthereof, wherein L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—. 5.The compound of claim 1, or a salt thereof, wherein: G¹ is —Ar¹-G^(a);Ar¹ is pyridinyl or pyrazinyl; and G^(a) is cyclopropyl.
 6. The compoundof claim 1, or a salt thereof, wherein: G² is Ar²; and Ar² is phenyl orpyridinyl; wherein Ar² is unsubstituted or substituted with 1 or 2substituents selected from the group consisting of halogen, cyano,C₁-C₄-alkyl, halomethyl, methoxy, and halomethoxy.
 7. The compound ofclaim 1, or a salt thereof, wherein: L′ is —C(R^(c))(R^(d))—,—C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)—, or —O—; R^(a) and R^(b), at eachoccurrence, are each hydrogen; R^(c) and R^(d) are each independentlyhydrogen or hydroxy; Ar¹ is, at each occurrence, independently selectedfrom the group consisting of phenyl, thiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, and benzoxazolyl; wherein Ar¹ is unsubstitutedor substituted with 1, 2, 3, 4, or 5 substituents selected from thegroup consisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy; G^(a) is cyclopropyl, cyclobutyl,or imidazolyl; L² is —S(O)₂— or —S(O)₂CH₂—; Ar² is aryl or heteroaryl;wherein the Ar² aryl is selected from the group consisting of phenyl,naphthyl, and tetrahydronaphthylenyl; the Ar² heteroaryl is selectedfrom the group consisting of furyl, thienyl, pyrazolyl, and pyridinyl;and Ar² is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of halogen, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u), —C(O)OR^(u),—C(O)N(R^(u))(R^(v)), and -G^(b); G^(b) is selected from the groupconsisting of cyclopropyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, and pyrazolyl; wherein the cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl are unsubstitutedor substituted with 1, 2, or 3 C₁-C₄-alkyl; R^(u) and R^(v) are, at eachoccurrence, independently hydrogen, C₁-C₄-alkyl, or C₁-C₄-haloalkyl; andAr³ is dihydroindenyl or dihydrobenzofuranyl, wherein the dihydroindenyland dihydrobenzofuranyl are unsubstituted or substituted with 1, 2, or 3C₁-C₄-alkyl.
 8. The compound of claim 1, or a salt thereof, wherein: G¹is —Ar¹ or —Ar¹-G^(a); R^(a), at each occurrence, is hydrogen; R^(c) andR^(d) are each independently hydrogen or hydroxy; Ar¹ is, at eachoccurrence, independently selected from the group consisting of phenyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, andbenzoxazolyl; wherein Ar¹ is unsubstituted or substituted with 1, 2, or3 substituents selected from the group consisting of halogen, cyano,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy; G^(a)is cyclopropyl, cyclobutyl, or imidazolyl; and L² is —S(O)₂— or—S(O)₂CH₂—.
 9. The compound of claim 1, or a salt thereof, wherein:R^(a) and R^(b), at each occurrence, are each hydrogen; R^(c) and R^(d)are each independently hydrogen or hydroxy; L² is —S(O)₂— or —S(O)₂CH₂—;G² is Ar²; Ar² is aryl or heteroaryl; wherein the Ar² aryl is selectedfrom the group consisting of phenyl, naphthyl, andtetrahydronaphthylenyl; the Ar² heteroaryl is selected from the groupconsisting of furyl, thienyl, pyrazolyl, and pyridinyl; and Ar² isunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of halogen, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u), —C(O)OR^(u), —C(O)N(R^(u))(R^(v)),and -G^(b); G^(b) is selected from the group consisting of cyclopropyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; whereinthe cyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;and R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl.
 10. The compound of claim 1, or a saltthereof, wherein: L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—; G¹ is Ar¹ or—Ar¹-G^(a); R^(a), at each occurrence, is hydrogen; Ar¹ is, at eachoccurrence, independently phenyl, pyridinyl, or pyrazinyl; wherein Ar¹is unsubstituted or substituted with 1, 2, or 3 substituents selectedfrom the group consisting of halogen, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl,C₁-C₄-haloalkyl, and C₁-C₄-haloalkoxy; G^(a) is cyclopropyl, cyclobutyl,or imidazolyl; L² is —S(O)₂—; G² is Ar²; Ar² is phenyl or pyridinyl;wherein Ar² is unsubstituted or substituted with 1, 2, or 3 substituentsselected from the group consisting of halogen, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, —OR^(u), —C(O)R^(u), —C(O)OR^(u), —C(O)N(R^(u))(R^(v)),and -G^(b); G^(b) is selected from the group consisting of cyclopropyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, and pyrazolyl; whereinthe cyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, andpyrazolyl are unsubstituted or substituted with 1, 2, or 3 C₁-C₄-alkyl;and R^(u) and R^(v) are, at each occurrence, independently hydrogen,C₁-C₄-alkyl, or C₁-C₄-haloalkyl.
 11. The compound of claim 1, or a saltthereof, wherein: L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—; G¹ is Ar¹ or—Ar¹-G^(a); R^(a), at each occurrence, is hydrogen; Ar¹ is, at eachoccurrence, independently phenyl, pyridin-2-yl, or pyrazin-2-yl; whereinAr¹ is unsubstituted or substituted with 1 or 2 substituents selectedfrom the group consisting of halogen, C₁-C₄-alkyl, halomethyl, andhalomethoxy; G^(a) is cyclopropyl; L² is —S(O)₂—; G² is Ar²; and Ar² isphenyl or pyridinyl; wherein Ar² is unsubstituted or substituted with 1or 2 substituents selected from the group consisting of halogen, cyano,C₁-C₄-alkyl, halomethyl, methoxy, and halomethoxy.
 12. The compound ofclaim 1, or a salt thereof, wherein: L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—,or —O—; G¹ is —Ar¹-G^(a); R^(a), at each occurrence, is hydrogen; Ar¹ ispyrazin-2-yl; wherein Ar¹ is unsubstituted or substituted with 1 or 2substituents selected from the group consisting of halogen, C₁-C₄-alkyl,halomethyl, and halomethoxy; G^(a) is cyclopropyl; L² is —S(O)₂—; G² isAr²; and Ar² is phenyl or pyridinyl; wherein Ar² is substituted with 1or 2 substituents selected from the group consisting of chloro, fluoro,trifluoromethyl, and trifluoromethoxy.
 13. The compound of claim 1, or asalt thereof, wherein: L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—; G¹ isAr¹ or —Ar¹-G^(a); R^(a), at each occurrence, is hydrogen; Ar¹ isphenyl, pyridin-2-yl, or pyrazin-2-yl; wherein Ar¹ substituted with 1 or2 substituents selected from the group consisting of chloro, fluoro,trifluoromethyl, and trifluoromethoxy; G^(a) is cyclopropyl; L² is—S(O)₂—; and Ar² is phenyl; wherein Ar² is substituted with 1 or 2substituents selected from the group consisting of chloro, fluoro,trifluoromethyl, and trifluoromethoxy.
 14. The compound of claim 1, or asalt thereof, wherein: L¹ is —C(O)NR^(a)—, —NR^(a)C(O)—, or —O—; G¹ isAr¹ or —Ar¹-G^(a); R^(a), at each occurrence, is hydrogen; Ar¹ isphenyl, pyridin-2-yl, or pyrazin-2-yl; wherein Ar¹ substituted with 1 or2 substituents selected from the group consisting of chloro, fluoro,trifluoromethyl, and trifluoromethoxy; G^(a) is cyclopropyl; L² is—S(O)₂—; and Ar² is pyridinyl; wherein Ar² is substituted with 1 or 2substituents selected from the group consisting of chloro, fluoro,trifluoromethyl, and trifluoromethoxy.
 15. The compound of claim 1, or asalt thereof, wherein L¹ is —O—.
 16. The compound, or a salt thereof, ofclaim 1, wherein the salt is a pharmaceutically acceptable salt.
 17. Thecompound of claim 1, or a salt thereof, wherein the compound is selectedfrom the group consisting of:4-fluoro-N-[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;4-fluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-4-fluorobenzamide;N-[(7S,8aS)-2-{[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-4-fluorobenzamide;4-chloro-N-[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;4-chloro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;4-chloro-N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;4-chloro-N-[(7S,8aS)-2-{[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;4-chloro-N-[(7S,8aS)-2-{[2-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-2,4-difluorobenzamide;2,4-difluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;N-{(7S,8aS)-2-[(2,4-dichlorophenyl)sulfonyl]octahydropyrrolo[1,2-a]pyrazin-7-yl}-2,4-difluorobenzamide;N-[(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]-3,4-difluorobenzamide;3,4-difluoro-N-[(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]benzamide;(7S,8aS)-2-[(3,5-dichlorophenyl)sulfonyl]-N-[6-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[1,2-a]pyrazin-7-amine;(7S,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[6-(trifluoromethyl)-pyridin-2-yl]octahydropyrrolo[1,2-a]pyrazin-7-amine;(7R,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-2-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)-pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-(pyrazin-2-yloxy)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethoxy)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(difluoromethoxy)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(difluoromethoxy)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-fluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-fluoro-5-(trifluoromethyl)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-furylsulfonyl)octahydropyrrolo-[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethoxy)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(8R*,8aS*)-8-[(5-chloropyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(8R*,8aR*)-8-[(5-chloropyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)—N-(diphenylmethyl)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide;(7S,8aS)—N-(diphenylmethyl)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide;(7S,8aS)—N-(diphenylmethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide;(7S,8aS)—N-(4,4,4-trifluorobutyl)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine-7-carboxamide;(7S,8aS)-7-[4-(trifluoromethoxy)phenoxy]-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-(4-tert-butylphenoxy)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[4-(1H-imidazol-1-yl)phenoxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(6-cyclopropylpyridazin-3-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(6-cyclopropylpyridazin-3-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(4-cyclopropylpyrimidin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(4-cyclopropylpyrimidin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;1-(4-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}phenyl)ethanone;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-fluoro-5-(trifluoromethyl)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-fluoro-3-(trifluoromethyl)-phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-chlorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(4-tert-butylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-tert-butyl-4-methoxyphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(morpholin-4-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(piperidin-1-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(pyrrolidin-1-yl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,4-difluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-5-(trifluoromethyl)benzonitrile;4-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-2-(trifluoromethyl)benzonitrile;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;2-chloro-5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;(7R,8aS)-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-2-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(5-tert-butyl-2-methoxyphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-methyl-2-thienyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(5-bromopyridin-3-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-cyclopropylpyridin-3-yl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(6-chloropyridin-3-yl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;5-{[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}-1,3-benzoxazole;(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;2-methyl-6-{[(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}-1,3-benzoxazole;(7S,8aS)-7-(4-fluoro-3-methylphenoxy)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-methylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(6-methylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-{[6-chloro-5-(trifluoromethyl)pyridin-3-yl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;6-{[(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}nicotinonitrile;5-{[(7R,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-yl]oxy}pyridine-2-carbonitrile;(7S,8aS)-7-[(6-bromopyridin-3-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(6-cyclopropylpyridin-3-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-bromopyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(6-bromopyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(6-cyclopropylpyridin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-bromo-1,3-thiazol-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropyl-1,3-thiazol-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3-difluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-fluoro-2-(piperidin-1-yl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(4-tert-butylbenzyl)oxy]-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-{[4-(trifluoromethoxy)benzyl]oxy}-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-{[4-(trifluoromethyl)benzyl]oxy}-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(1,1-difluoroethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclobutylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclobutylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-(biphenyl-3-ylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-isopropylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-methoxyphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-methoxy-3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;1-(3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}phenyl)ethanone;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(1,1-difluoroethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-2-{[3-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2,3-dihydro-1-benzofuran-5-yl-sulfonyl)octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-tert-butylphenyl)sulfonyl]-7-[(5-isopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4,5-trifluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-fluoro-5-methylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,6-difluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3,4-trifluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(5-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-fluoro-4-methylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-difluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-dimethylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-2-{[4-bromo-3-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-fluoro-2-methylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(4-chloro-2-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)-oxy]octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-difluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-chloro-4-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(4-bromo-3-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-2-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(mesitylsulfonyl)octahydropyrrolo-[1,2-a]pyrazine;(7S,8aS)-2-(biphenyl-4-ylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-bromophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-{[2,5-bis(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-fluoro-2-methylphenyl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dichloro-3-thienyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(5-chloro-2-thienyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(4-chlorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-fluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-fluorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3-methylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;2-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methoxyphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,5-dichlorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,3-dichlorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(4-bromophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4-dichlorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dichlorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;4-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,4-dichlorophenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(1-naphthylsulfonyl)octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-naphthylsulfonyl)octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-propylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2-methylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(2,5-dimethoxyphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(3-chloro-4-fluorophenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-1-methyl-1,3-dihydro-2H-indol-2-one;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-ethyl-2-thienyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(1-ethyl-1H-pyrazol-4-yl)-sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(2-cyclopropylpyrimidin-4-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(2-cyclopropylpyrimidin-4-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(5-tert-butyl-2-methylphenyl)sulfonyl]-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methoxy-3-methylphenyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-{[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-methoxy-5-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2,3-dihydro-1H-inden-5-yl-sulfonyl)octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,4-dimethylphenyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(1-methyl-1H-pyrazol-5-yl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-methyl-6-(trifluoromethyl)-pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[2-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(methoxymethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-methyl-3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-2-fluorobenzonitrile;2-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-4-methylbenzonitrile;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(1-isopropyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}-7-ethoxyoctahydro-pyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(3,3,3-trifluoropropyl)-sulfonyl]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-(butylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(2-thienylsulfonyl)octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-(benzylsulfonyl)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-(isopropylsulfonyl)octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-3-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4-methylpyridin-2-yl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(6-methoxypyridin-3-yl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;3-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-N,N-dimethylbenzamide;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(5-fluoropyridin-3-yl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;5-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;2-{[(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}-4-(trifluoromethyl)benzonitrile;(7S,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-2-[(6-tert-butylpyridin-2-yl)sulfonyl]-7-[(5-isopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}-2-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[6-(trifluoromethyl)pyridin-2-yl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-{[5-(1-methylcyclopropyl)pyrazin-2-yl]oxy}-2-{[3-(trifluoromethyl)-phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazine;7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(7S,8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(8aS)-7-(3-fluorobenzyl)-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(8aS)-7-(3-fluorobenzyl)-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(7S,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(7S,8aS)-7-[(3-fluorophenyl)(hydroxy)methyl]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)pyridin-2-yl]-oxy}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)benzyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7S,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[(4,4,4-trifluorobutyl)sulfonyl]-octahydropyrrolo[1,2-a]pyrazine;(8aR)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(8aS)-7-[3-(trifluoromethyl)benzyl]-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;(8aS)-7-[3-(trifluoromethyl)benzyl]-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;3-{[(8aS)-6-oxo-7-[3-(trifluoromethyl)benzyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;3-{[(7R,8aS)-7-{[5-(trifluoromethyl)pyridin-2-yl]oxy}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;(7S,8aS)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;3-{[(7R,8aS)-7-{[6-(trifluoromethyl)pyridin-3-yl]oxy}hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]sulfonyl}benzonitrile;(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[6-(trifluoromethyl)pyridin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine;and(7S,8aS)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-7-{[5-(trifluoromethyl)pyridin-3-yl]oxy}octahydropyrrolo[1,2-a]pyrazine.18. The compound or salt of claim 1 that is(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine,or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier.
 20. Thepharmaceutical composition of claim 19, wherein the compound orpharmaceutically acceptable salt thereof is(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}-octahydropyrrolo[1,2-a]pyrazine.21. A compound of Formula (II):

or a salt thereof, wherein: R²¹ and R²² are independently selected fromthe group consisting of hydrogen, C₁₋₃ alkyl, and cyclopropyl; and oneof R²³ and R²⁴ is hydrogen, and the other of R²³ and R²⁴ is halomethyl.22. The compound of claim 21, or a salt thereof, wherein one of R²³ andR²⁴ is hydrogen, and the other of R²³ and R²⁴ is trifluoromethyl. 23.The compound of claim 21, or a salt thereof, wherein: R²¹ is hydrogen;and R²² is selected from the group consisting of hydrogen, isopropyl,and cyclopropyl; and one of R²³ and R²⁴ is hydrogen, and the other ofR²³ and R²⁴ is halomethyl.
 24. The compound of claim 21, or a saltthereof, wherein: R²¹ is selected from the group consisting of hydrogen,isopropyl, and cyclopropyl; and R²² is hydrogen; and one of R²³ and R²⁴is hydrogen, and the other of R²³ and R²⁴ is halomethyl.
 25. Thecompound of claim 21, or a salt thereof, wherein the compound isselected from the group consisting of:(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-(pyrazin-2-yloxy)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}-octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;(7R,8aS)-7-[(6-cyclopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine;and (7R,8aS)-7-[(5-isopropylpyrazin-2-yl)oxy]-2-{[4-(trifluoromethyl)phenyl]-sulfonyl}octahydropyrrolo[1,2-a]pyrazine.